Journal of Liver

Tripartite Motif Cofactors, a Novel Gene Target for Liver Cancer via Regulating the Immune Cells and Gut Microbiome: A Review

Ifeoma P Okoli^{1,2* 1}Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, 211198 Nanjing, China
²Department of Pharmacology and Therapeutics, Umuna Orlu Campus, Imo State University, Owerri Imo State, Nigeria
^*Correspondence: Ifeoma P Okoli, Department of Pharmacology and Therapeutics, Umuna Orlu Campus, Imo State University, Nigeria, Tel: +2348037985383, Email:

Received: 14-Aug-2019 Published: 14-Oct-2019

Abbreviations

TRIM: Tripartite Motif; ALD-Alcoholic Liver; NAFL: Nonalcoholic Fatty Liver; NASH: Nonalcoholic Steatohepatitis; PHD: Plant Homeodomain/Bromodomain; RBCC: Ring B-Box and Coiled Coil; KRAB-Znfs: Kruppel-Associated Box Domain Zinc Fingers; KAP1-KRAB: Associated Protein 1; PBC: Primary Biliary Cirrhosis; AIH: Autoimmune Hepatitis; GWAs: Genome-Wide Association Studies; H3K9me3: Histone-3- Lysine 9 Trimethylation; IPSCs: Induced Pluripotent Stem Cell; KLF4-Kruppel-Like Factor 4; NR-Nuclear Receptor; AF-2: Activated Function-2; MSK1: Mitogen-And Stress-Activated Protein Kinase; FSP27: Fat Specific Protein 27; HCMV: Human Cytomegalovirus; ATM: Ataxia Telangiectasia Mutated; PAF: Pol 11-Associated Factor; POL 11: Pausing of RNA Polymerase 11; ULU: Upper Limit of Normal; ALT: Alanine Transaminase; ALP: Alkaline Phosphatase; BBV: Blood-Borne Virus; SNP: Single Nucleotide Polymorphism; aCGL: Array Comparative Genomic Hybridization; CNV: Copy Number Variation; TFs: Transcription Factors; RARA: RAR α Receptor; NF-kB: Nuclear Factor Kappa Beta; PRR-Pattern Recognition Receptor; TLR-Toll-Like Receptor; MDR2-Multi Drug Resistance Protein 2; CBA-Conjugated Bile Acid; SIPR2-Sphinogosine 1-Phosphate Receptor 2; TcF/LEF-T-Cell Factor/ Lymphoid Enhancer Factor; GSK2β: Glucose Synthase Kinase 3 Beta; APC: Adenomatous Polyposis Coli; TKR: Tyrosine Kinase Receptor; TGFβ: Transforming Growth Factor; RB1: Retinoblastoma B1; IGF2R: Insulin-Like Growth Factor 2 Receptor; hESCs-Human Embryonic Stem Cell; PNPLA3: Patatin-Like Phospholipase Domain Containing 3 Protein; HSD17B13: Hydroxysterol 17-Beta Dehydrogenase 13; CYP7A1: Choleterol 7α Hydroxylase; CYP7B1: Cholesterol 7α Hydroxylase β1; CYP27A1: Sterol 27 Hydroxylase A1; OCA: Obeticholic Acid; CDCA: Chenodeoxycholic Acid; MCA: Muricholic Acid; FXR: Farnesoid X Receptor; CA: Cholic Acid; TCA: Taurocholic Acid; GCA: Glycocholic Acid; TCDCA: Taurochenodeoxycholic Acid; GCDCA: Glycochenodeoxycholic Acid; UDCA: Ursodeoxycholic Acid; DCA: Deoxycholic Acid; LCA: Lithocholic Acid; FGF: Fibroblast Growth Factor; BDA: Bile Duct Obstruction; ERK1/2: Extracellular Signal-Related Protein Kinase 1/2; T2D: Type 2 Diabetes; GPCRs: G Protein Coupled Receptors; Atg16L1: Autophagy Related 16 Like 1; SARM: Senile Α- and Armadillo-Motif; IRF3: Interferon-Regulatory Factor 3; TIR: Interleukin 1 Receptor- Domain-Containing Adaptor Protein; TRIF-TIR Domain-Containing Adaptor-Inducing Interferon B; PAMP: Pathogen Associated Molecular Pattern; MAMP: Microbe Associated Molecular Pattern; LPS: Lipopolysaccharide; LTA: Lipoteichoic Acid; IL: Interleukin; IFN: γ-Interferon Gamma; SIBO: Small Intestinal Bacterial Overgrowth; CTL: Cytotoxic T Lymphocyte; CGZB: Cytotoxic Granzyme B; BCL-2: B Cell Lymphoma 2; TNF: Tumor Necrosis Factor; CMML: Chronic Myelomonocytic Leukemia; Cvt: Cytoplasm-to-Vacuole Targeting; α-TEA: Alpha-Tocopheryloxy Acetic Acid; NPC: Non-Parenchymal Cell; HSC: Hematopoietic Stem Cell; TSP: Tissue Specific Phenotype; C/EBPβ: CCAAT Enhancer Binding Protein Beta; STAT3: Signal Transducer and Activator of Transcription 3; AP-1: Activator Protein 1; LrNK: Liver Resident Natural Killer Cell; Treg: Regulatory T Cell; FOXP3: Forkhead Box P3; STARTRAC: Single T Cell Analysis By RNA-Seq and TCR Tracking; TME: Tumor Microenvironment; ATM: Anti Tumor Immune; HMGB1: Membrane Bound High Mobility Group B1; HLA-C1: Human Leukocyte Antigen–C Group 1; CNV: Copy Number Variant; KOX1/ZNF 10: Human Zinc Finger Factor 10

Background

Liver being important organ in the body, perform great function yet stand-alone, in disease state fear troupe in and one cannot mention liver cancer without the diseases of the liver. Liver cancer (cancer that starts in the liver) are disorders that begin in the cells of the liver, those that begin in other areas of the body and spread to the liver are termed metastatic. Hepatitis ABC, cirrhosis and alcoholic are leading in liver cancer, which ranked three high causes of death [1-3]. Liver cancer disorder, face with two complexes histologic pattern [4]. Clinical features like alcohol and nonalcoholic fatty liver that includes NAFL (fatty liver without damage) and nonalcoholic steatohepatitis NASH (obesity, lipid metabolism disorders, insulin resistance). That presented with histological activity in both grade and stage (fatty liver and steatohepatitis) and clinical association specifically on etiology (insulin resistance, lipid, alcohol and drugs) with natural history and mechanism varies [4].

Classification of liver diseases seems difficult because no best way to classify fatty liver disorders, with guidelines on recent research articles can distinguish based on overlapped syndrome between PBC and AIH [5]. This report suggested that implication for AIH therapy, not at classification point alone. However, fatty disorders are been classified as alcohol and nonalcoholic but not known if the pathologic condition of overlapping expression represents steatohepatitis and other criteria [4,6].

Globally, liver diseases have recorded the highest death rate and there is a need to identify the key gene that plays roles in its onset and development. Common types are hepatocellular carcinomas develop from liver cells (hepatocytes) which present with cirrhosis, viral infections [1,2,7], and steatohepatitis. Cirrhosis, hepatitis B, C virus (HBV, HCV) which tends to be most deadly among all other types and cholangiocarcinoma develop from the bile duct, although the rate of progression varies from individual. Gene disorders and metabolic syndrome remain the key genesis of this deadly disease [8-11]. Genetics factors are at high risks, which contributed 10-30% heritability in GWAs and account to between 30-50% in disease prevalence like obesity, cirrhosis, T2DM [12].

Genome-wide association study identified large amount of genetic variant associated with various human disease that cluster in families, these were present with heritability risk loci provided on a sample number in a population [13] To explain genetic influence on common diseases and heritability in human disease-associated variant mostly occur in protein coding region than on genotyping array. Of which various compatible approaches has developed to incorporate analysis of CNV in design array and linkage disequilibrium relationship between common copy number polymorphism CNPs and SNPs data [13-16].

Tripartite motif family protein classifies into eleven subgroups of C-1-X1, among all TRIM24, TRIM28, TRIM33 are in the same subgroup C-VI [17-19]. Emphatically, a subgroup of tripartite motif TIF1β is in-relation with TIF1α, though TIF1γ on which the genetic influence identified [20,21]. Notably, interferon IFN upregulate the expression of the various TRIM gene and trigger an antiviral response. However, are not induced by IFN in some and were not detected in few others like TRIM1, TRIM11, TRIM28 and TRIM62 [18]. Remarkably, in human monocyte-derived macrophages, interferon type 1 downregulated the expression of TRIM28, whereas type 2 induces downregulate of TRIM28 [18]. Other study observed cross-link of Fϲγ by immune complex IC which negatively regulate IFN-induced signaling, in the sense IC-mediated mechanism inhibited by IFN gamma signaling [22], whereas TRIM9 and TRIM54 upregulated in fc region of IgG receptors FϲγR-activated macrophage [18]. Furthermore, the study identified risk loci as PNPLA3 for ALD and TM6SF2, also MBOAT7 [23,24], considering their combined effect as a genetic risk factor for NAFLD [25]. Moreover, TRIM 28 and a subset of KRAB-ZNFs identified a regulator of DNA methylation on reprogramming as KRAB/ZNFs interact with TRIM28 to induce H3K9me3 DNA methylation [26-28]. Identified as a repressor, modulator [21,29], coactivator [30], DNA repair [20], tumor suppressor [20] and corepressor [31-34]. Noteworthy, kruppel-like factor 4, a protein known for pluripotency and reprogramming induced pluripotent stem cell, differentiation depends on cell status which represses gene expression, thus involve in various pathway together with TRIM28 by modulating H3K9me3 DNA methylation and somatic cell are reversible [26].

TRIM24 interact with the ligand-binding domain, a different NR ‘retinoic acid’ receptors RAR [35], mediator of AF-2 to chromatin remodeling [36] and Msug1 [37], of which RA signaling altered in HCC developed TRIM24 knockout mice [38]. Remarkably, major pathway for liver carcinogenesis implicated by p53 inactivation via TP53 mutation gene, activation of Wnt-β catenin pathway via CTNNB1/β-catenin, have both positive and negative regulatory role on AXIN1 [39-41]. Thus knockout mice genetics showed an increase of HCC which are significantly implicated (RARA) in liver-specific cancer [38]. Importantly, the study has shown a familial clustering at an early age of onset of liver cancer developed to HCC and major gene involved [42,43]. Mendelian autosomal recessive major genes identified to a play role in HCC etiology [42]. Thus, TRIM24 inactivation promotes tumorigenesis showing cellautonomous process [20,21].

TRIM28 interact with kruppel-related zinc-finger transcription factor known for DNA repair and transcription regulation. TRIM28 acts as a tumor suppressor whereas function as oncogene [20,21]. DNA damage recognition by ATM and initiation of genotoxic stress response [44,45]. Also in response to recognition and repair of DNA-damage that modulated by heterochromatin protein 1 to histone, suggests its involvement in DNA damage response pathways [34,46,47]. Consistent with ATM- and KAP1- independent pathways of chromatin relaxation in the DNA damage response may have been from phosphorylation of serine 824 [44]. The KAP1 localization at sites of DNA strand break response to ionization radiations, signaling pathway could be the perfect way of ATM- and KAP1- in DNA repair [34]. Recently study identifies TRIM28 (KAP1) role as cofactor and regulator to myoblast differentiation MyoD function of which phosphorylation of KAP1 mediated by MSK1 thereby releases corepressor from the scaffold [48]. A heterochromatin-induce activity of KAP1 was suppressed by mTOR-mediated phosphorylation driven by KAP1 knockdown of latency either by activation of NF-KB with immune-based drug and ATM combination [33]. TRIM28 have increased tendency to tolerate environmental stress thus serves as link between gut microbiota and liver cancer which FXR inactivation, increase BAs levels contributed to inflammation and tumorigenesis in TRIM28 hepatocytes [49]. Environmental factors as diet and infection are main element involved diseases of liver, noting the closure of the microbes live in the intestine. Gut microbiota play roles in chronic inflammation of liver disease thus influence liver phenotype in various ways. Gut microbiota activated TLR/NLR that motivate expression of pro-inflammatory gene thereby promote liver inflammation [50]. Knockdown of KRAB-associated protein 1 KAP1 (liver-specific) showed similarities at FSP27 gene site and detoxification, of note male are particularly being challenged [31]. It is essential KAP1 identified as corepressor that phosphorylate on serine 824 human cytomegalovirus infect cells thus inhibited by mammalian target rapamycin mTOR, effect enhanced by addition of NF- KB inducer (TNF) [33]. HCMV latency may have driven by pharmacological activation of ataxia telangiectasia mutated (KAP1).

TRIM33 interact with SMAD4 act as tumor suppressor gene of chronic myelomonocytic development plays a role in preventing apoptosis in B cells lymphoblastic leukemia [51]. The study has been reported that trim 33 act as an oncogene [51-53], although depends on the cell type and as tumor suppressor [54-56]. Various researches have reported its involvement in blood cancers [51,55,57], which was shown to interact with TRIM24. Study observed loss of TRIM^{- /-} prevent apoptosis thereby blocked the enhancer-mediated Bimactivation and functions as a negative regulator to the activity of the enhancer [51]. In addition, loss of function of pausing of RNA polymerase II-associated factors PAF in trim gamma-deficient mice, which reduced hematopoietic stem cells HSC function and blood defects [58,59]. Deficient embryos of trim 33 was unable to give responses to inflammatory recruitment signals at the site of infection and decreased basal motility showing involvement in inflammation in both macrophages and neutrophils [60]. Accordingly, PHD-bromodomain identified, which binds histone H3 tail in order to recruit trim 33 to the chromatin and E3 ligase stimulation, also have ability to ubiquitinate Smad4 complex at TGF-β superfamily [61]. Furthermore, loss of trim33 was identified in chronic myelomonocytic leukemia CMML mice, although could not detects mutation in the coding sequence of gene which may be as a result of the reduced expression in 35% patients with CMML that goes almost undetected [55]. The expression of Trim33 restores monocytes in a patient who respond to demethylating agent decitabine. Furthermore, trim 33 prevented apoptosis in B lymphoblastic leukemia, achieve by blocking activation of enhancermediated Bim (proapoptotic protein gene), also recruited by Pu.1 yet antagonize its function [51]. Importantly, significant deletion of the region at chromosome 1p13.1 in the myelomonocytic patient was also reported [62]. Despite the small size of aberration, deletion 1p has reported for showing most abnormalities of which have also identified with trim 33 at 1p13.1 thus seen in myelomonocytic patients [56,63,64]. Trim 24 and 33 showed to form a complex that in turn suppress tumor in HCC (Figure 1) [20,21].

Figure 1: Protein-protein interaction (PPI) network analysis.

TRIM sub-family proteins: C -terminal domain

TRIM, a multi domain protein associated with N-terminal (ring finger E3 ligase) and C-terminal (bromodomain PHD chromatin) interacting module known as B-boxes and coiled coil domain with structure that underscores biochemical reaction. TRIM 24,28,33 are three member family that have PHD signature and nuclear protein which forms multimeric complexes for transcription and remodeling and distinct transcriptional factors that correct with each other and interact with other proteins both functional and physical in cancer diseases [20].

Tripartite motif family proteins classify into 11 subgroups of C-1 - X1, among all Trim24, Trim28 and Trim33 are in the same subgroup C-V1 (Figure 2).

Figure 2: Structural classification of tripartite motif family protein.

The risk factors and current mechanism of the liver cancer

The risk factors:

Cirrhosis: Cholangitis as formerly known refer now PBC, an autoimmune disease of liver [65]. Cholestasis liver present symptoms like fatigue [66], pruritus [67], portal hypertension [68], hyperlipidemia [69], bone disease [70], vitamins deficiency [71]. Classical features causes intrahepatic bile duct damage, inflammation of portal and periportal (interface hepatitis) and later to fibrosis (fibrous septa) with three scores (portal, bridging and perisinusoidal fibrosis) of complex features eventually develop (as scarring) to cirrhosis [4,65,72,73]. Further study report its development from cholestasis to fibrosis and finally to cirrhosis [74]. The PBC prevalence showed an increase in families with affected member possibly environmental factors such as chemical and infection can induce PBC [75,76]. Cholangiocytes is the cells involved in cholestasis liver diseases representing clinical features as PBC that may progress to autoimmune hepatitis not significant; some patient may present with both PBC and AIH. Other features base on cholestasis serum liver test, outline of positive non-cholestasis liver injury. PBC usually presented with antinuclear antibodies ANA, pathology of intrahepatic bile duct in 90-95% patients [73,77], anti-smooth muscle antibody ASMA test (increase immunoglobulin IgM and hyperglobulinemia IgG) and histology presenting features such as elevated upper limit of normal in ALT, ALP, anti-mitochondrial antibody AMA (negative/positive) [73]. Given that AMA presented in 95% of PBC patients [78], of which magnitude of biopsy (showing bile duct and non-suppurative cholangitis damage) sample is necessary for diagnosis. Treatment with immunosuppression and ursodeoxycholic acid UDCA are normally used to aid autoimmune overlap syndrome in diagnosis [5,79]. Given that risk of reduction of pruritus in UDCA therapy with rifampin showed no significant in PBC patients other than rifampin associated with hepatotoxicity [67].

Treatment of PBC based on elevated alkaline phosphatase level is the current diagnosis, as ursodiol was only treatment approved for primary biliary cirrhosis, thus concomitant administration with obeticholic acid OCA showed decrease alkaline phosphatase and bilirubin level baseline [80]. Other study indicated a significant increase in reactive oxygen specie ROS and apoptosis in hepatocytes in Ghr^-/- and Mdr2^-/- knockout mice compare to control, thus showed highly downregulation in hepato-protective gene of Hnf6, Egfr [81]. Expectedly, an increase in serum material associated with liver damage and cholestasis in Ghr^-/- and Mdr2^-/- knockout mice, increase collagen deposition and bile duct proliferation related to Mdr2^-/- knockout mice [81]. Importantly, link between HLA allele and PBC has been reported [82-84], risk allele occur in gene associated with immune function that intersect in various immune pathways, which identified in GWAs study as B, T, myeloid cell differentiation and antigen presentation [85]. Noting that three loci gene in TNF-α signaling pathway identified by GWA study: TNFRSF1A, DENND1B, TNFAIP2 [82,86]. Study revealed of insulin resistance and cirrhosis in NAFLD patients compared to control with a familiar clustering and potential maternal linkage [12,87]. Another study reported of HCV related with odd ratio 17; 95% Cl, 4.2-12.9 significant increase prevalence of cirrhosis among first degree patients relative [88], also other genetic evidence of linkage in patients with HBV related HCC [89]. In addition, identified PNPLA3 [90], TM6SF2 [91], SAMM50 [92], ERLIN1 [93] association in liver disease. Recently studies also identify SLG39A12 encoding solute carrier family 39 member12, GPT and GOT1 encoding AST and ALT respectively [94].

Profoundly, PBC recurrent reported in 25% of patients, which occurred after liver transplant [73]. Liver biopsy is needed for diagnosis of post-transplant to certain AMA persistence, thus preventive treatment reduces risk of recurrent with UDCA after transplant although not confirm yet [95]. Whereas treatment other than clinical and characteristics risk factors has been confirmed. Study have established that chronic liver inflammation motivated by HCV, HBV, NAFLD and alcohol intake awaken by HCC should targeted at early detection, prevention and surveillance [96], which can restrict and activate immunity of neoantigen-specific T cells in immunotherapy [97], and inflammation associated as key hallmark of cancer (Figure 3) [98].

Figure 3: Stages of primary biliary cirrhosis.

Hepatitis B and C: Hepatitis is a disease that affects the liver, which threatens the liver ability to function having different symptoms and treatment. Various types are A, B, C, D and E, laboratory tests can determine hepatitis types. Causes include virus, recreational drugs, injury and contact with infected person. Here we are going to focus on hepatitis B and C types that tend to be more dangerous than others are. Hepatitis B spread mainly through blood contact with infected or mother to infant delivery, which can lead to serious health issues like cirrhosis that risks related to age. Acute hepatitis B virus HBV estimated at 20,900 cases, while chronic HBV estimated at 2.2 million cases in United States 2016 [99,100]. Hepatitis C is a blood-borne virus spread by sharing sharp objects and drugs injecting equipment. Chronic HCV also can be acute or chronic even death. Acute HCV estimated at 41,200 cases, which can become chronic in 75-85% cases [100,101], people living with HCV estimated at 2.4 million in 2013-2016 in United State [102,103], histological stage and advanced fibrosis score in PBC associated with HBV infection [104]. Studies suggested that some host factors such as immunity could be acquire to protect against viral HCV persistence [105], and reinfection risk after repeated clearance associated with previous infection and HCV-specific T-cells [106]. Suggest that vaccine for spontaneous clearance more preferable than vaccine for primary HCV prevention (Figures 4 and 5).

Figure 4: Acute viral Hepatitis B surveillance-US. CDC-All age groups, all races/ethnicities, both Sexes.

Figure 5: Acute viral Hepatitis C surveillance. CDC-All age groups, all races/ethnicities, both sexes.

Alcoholic, nonalcoholic and steatohepatitis: Two histologic patterns in NAFLD reported by Sanyal et al. are steatohepatitis and fatty liver disease although classified traditionally as alcoholic and nonalcoholic, of which nonalcoholic include both NAFL, NASH [4], study emphasized as an active NAFLD present with hepatic necroinflammation and fibrosis progression [107]. Obesity, lipid metabolism disorders, insulin resistance associated with NAFLD and other risk factors [108]. Worldwide estimates NAFLD prevalence at 25.24% high in Middle East, South America and low in Africa [24,109]. Nonalcoholic fatty liver disease prevalence ranked between 19-46% [110,111], which has continued to increase [112]. In addition, between 10 million people estimated coexist with NAFLD and diabetes in United States of note clinical variables can be employ as a guide in referral [113]. Metabolically, a syndrome associates insulin resistance, T2D, obesity as major risk factor [8,109], moreover hyperlipidemia, high blood pressure, diabetes and metabolic syndrome however inclusive [109]. Study established that low T1D and high in T2D prevalence in NAFLD could be latent autoimmune diabetes [114]. Furthermore, childhood and adolescence overweight associated with NAFLD, also in lean patient of which environmental factors such as high fructose, high fat diet and genetic term the cause. Endocrine disorder and drugrelated cause also reported [24]. PNPLA3, MBOAT7 and TMC4 have been associated with NAFLD [24], TM6SF2 identified in another studies [24,107]. Elevated level of TRIM24 reported in HCC of note originally termed transcription intermediate factor α TIF1α [115].

Disorder and fat accumulation in liver can generate to NAFL (usually present with fatty liver) and progressive subtype of NAFLD called nonalcoholic steatohepatitis NASH (present with fatty liver and inflammation, scarring leads to cirrhosis, hepatocellular carcinoma HCC and death associated with older age). The liver cells being replaced by scar tissue as a result of severe damage unable to function well determine by liver biopsy in NAFLD patients which may progress to cirrhosis [109,116,117], noting that NAFL cause globally liver disease. Nonalcoholic steatohepatitis quite significant using a diagnosis of NAFLD to establish prevalence and progression creates challenges for screening not keeping out origin as alcohol intake, hepatitis for fatty liver [109]. Studies further review factor contribute to NASH development like environmental and genetic factors of gene association with adiponutrin/PNPLA3 genotype associated with NAFLD progression to necroinflammation and fibrosis [24,118], and TM6SF2 through increased hepatic triglyceride [24,107,119]. SNP array development technologies for profiling common variant made it easier for GWAs approach in identifying risk genetic variant associated with ALD and NAFLD probable better than candidate gene approach [6]. Farnesoid X nuclear receptor (agonist OCA) showed efficacy, improve biochemical and histological feature in NASH, noting pruritus on 23% patient and overall increase in some cholesterol levels suggest be heated by positive findings [8]. Histological features for NAFLD include steatosis, necroinflammation and fibrosis, with tendency to progress from NASH to cirrhosis and other liverrelated complications especially NAFLD low activity scores [107]. Obeticholic acid, a semi-synthetic BA analogue (CDCA) and natural FXR and NR agonist [120]. Study establish that alkaline phosphatase and bilirubin level of 5-10 mg daily doses of obeticholic acid decrease in primary biliary cholangitis patients at phase 3 trial (56% 5-10 mg, 68% 10 mg, 38% placebo), for 12 months resulted with pruritus [80]. However, daily doses (50 mg) OCA for 2 weeks at phase 2 trial showed greater decrease and pruritus greatly severe, UDCA has remain approved treatment for PBC [72]. Study find that in overall patients 27% progressed to fibrosis, 48% with static disease and 25% with fibrosis regression [107], consistent with another study showing that in overall patients 42% progressed to fibrosis, no change seen in 40%, 18% regressed to fibrosis [121]. The grading and staging of NASH are not been validated, although grading classified from 1-4 base on fibrosis degree [4]. NASH presence, stage of fibrosis on prognosis showed no increased liverspecific morbidity and mortality, which can use in individual patient counseling and generally (Figure 6) [122].

Figure 6: Progression of NAFLD–Cirrhosis.

Hepatocellular carcinoma: Primary liver disease associate with death in cirrhosis from chronic liver inflammation development have been link to hepatitis BC infection. The incidence on liver diseases like cirrhosis follows likely pattern of variation with same etiology factors [123], that account between 70% to 90% of primary liver diseases [124], occur in 1-6% of PBC patients annually. The risk factors include male gender [124,125], old age, advanced histological stage, portal hypertension [126], and biochemical nonresponses to UDCA [127-129]. Other risk factors recognized are hepatitis B, C, alcoholic liver disease, NASH, blood transfusion [128], metabolic syndrome [124], and adenomatous hyperplasia as a precursor of HCC presented with malignancy disorder [130], lymphocytic piecemeal necrosis also associated with HCC. DNA methylation is important in development of tumor cells, it is necessary to ascertain when demethylation and hypomethylation occur during tumorigenesis. Study had it that hypomethylation occurs in HCC, which confirm of DNA from chemically induced hepatocarcinomas compared to DNA of normal rat liver, that showed an extensive demethylation of DNA in tumor progression [131]. More so, the degree of methylation nonmetastatic tumor is same as in normal prostate DNA, age not ascertain [132] Study showed higher degree of genomic wide hypomethylation associated with late grade in HCC which progresses in tumor size throughout life time [133], transposable element in HCC activated via genome-wide hypomethylation not ascertain. Reduction in genome scale DNA methylation and tend to distinct global DNA methylation level which can be used as a predictor in severe or complicated cancer types, [134] reveals common cancer hallmarks and specific DNA methylation pattern [135]. Alcohol consumption also accounts one of factors at high risk associated with HCC development in liver cancer [124], comparing HCC patients with NASH at 2.6% and NASH with cirrhosis at 4.0% per annual [117]. Patient with advance stage of primary biliary cirrhosis are at great risk for hepatocellular carcinoma development thereby requires surveillance, using known clinical variables which includes male sex, advanced age, portal hypertension, previous blood transfusion and stage of histology [128].

The incidence of specific (hepatobiliary) malignancy in PBC patient is at increased risk of developing cancer especially an advanced histologic stage at increased frequency [136], with evidence of low increase in overall cancer except liver cancer showing high prevalence and mortality in PBC patients [137]. Adding that HCV super infection may play roles in HCC development and history of cigarette smoking indicated on logistic regression analysis [138], more so, development HCC in PBC patient associate with 12 months biochemical nonresponses [127]. Study suggests of long term aggressive therapy in PBC patients may prevent HCC development [129]. Some strategies suggested proven effective and economic in preventive approaches to reduce risk of cancer incidence than treating an already advanced development of cancer , thus prescreen cancer patients at high risk more likely to benefit from preventive strategy [139]. Of note inflammation can impacts every single step of cancer development and progression even response to therapy. Whereas cytokines as a prognostic biomarkers contribute to a tumor microenvironment that permissive to cancer progression and related to drug resistance, which can disrupt long term success of treatment of cancer [140]. Anti-immune checkpoint inhibitors developed to avoid immunopathological diseases has been define for over active immune response and unsuitable reaction [141]. Active anti-tumor immune responses and modulators of specific genes have been associated successful oncotherapy either by presenting tumor antigen to activate or reactivate the adaptive antitumor immune responses [142]. The pro-inflammatory cytokines induction and activation of antigen-presenting cells associated with tumor ablation, thus immune defense that are targeted by immunotherapy showed effect in treatment[143]. Study of Yue et al. showed that immune system can educate cancer and suppress immune response and condition microenvironment provides interaction between HCC and immune system using patients-derived xenograft HCC-PDX technologies [144]. HSD17B13 rs7261567: TA associate reduced risk ALD, NAFLD, alcohol and nonalcoholic cirrhosis and lower odds of HCC (p꞊0.047) [94]. Study showed half of patients with advanced HCC have high levels of AFP that shows poor prognostic indicator and high rate recurrence in HCC patients with liver diseases. Although an advanced combine treatment using systemic therapy such as nivolumab and durvalumab expected to be more efficacious than single agents which absorption will be, oblige by safety and tolerance [7].

The current mechanism

Over last few years, identification of genetic diversity using various genomic analysis platforms such as SNP and aCGH. Of which CNV being at high-resolution microarray platforms to identify gene associated with various diseases in human. Genetic alteration and gene expression profiling analysis have provided information on the gene involve in various liver cancer [39]. As a result, various genes identified to associate in liver cancer such as tripartite motif-containing 24, 28 and 33 protein [21,145]. The DNA alteration of copy number variations involved has been identified in various human diseases and evolution [146], which are been used in diagnosis of complex human diseases [147]. Among CNV-driven genes identified, 8 of known cancer-related TFs which interact with 21CNV-driven gene, trim28 were included [145]. Identifying signaling pathways in liver carcinogenesis will provides new molecular target for therapy, such signaling pathways includes Hedgehog, Wnt-β-Catenin, tyrosine kinase receptorrelated pathways and propose becoming current molecular-based target for HCC treatment [39]. Of note the elevated nuclear β-catenin correlate with transcriptional target gene expression regulated by alternate signaling pathways in HCC that play roles in tumor progression and cell adhesion [39,148]. More so, increase retinoic acid signaling, activate single allele RARA and correlate with carcinogenic process which was able to completely restored suppressed hepatocarcinogenesis and expression of RA target genes at normal rate of hepatocytes proliferation [21,29]. Noteworthily, in a combinatorial and signal dependent way, KAP1/MyoD/Mef2D axis identified at transcriptional regulatory system [48].

The dysregulation of immune responses are associated with pathophysiology of various diseases incudes liver cancer. Study established link between inflammation, cancer development and progression as promoter [149,150], noting that NF-KB transcription factor serves as mediator of inflammatory process, play roles in innate and adaptive immune response [149,151]. Activation of nuclear factor (kappa B) in cancer diseases was associated in genetic alteration [149]. Whereas, proposed factors influencing signal-transduction mechanism in cancer that affect host through PRRs, regulate immune responses (innate and adaptive) and enzymes control expression gene encoding cytokines, chemokine [152], belonging to TLR family [153]. NF-KB either promotes or inhibits carcinogenesis on which inflammation and infection can enhance cancer development through signal-transduction mechanism influence in cancer surveillance and malignancy. Not with standing, NF-KB as a transcriptional regulator and seems to be the most signaling pathways that activated by infection, inflammation that can promote tumor in chronic inflammation and infection [154]. But specifically, in knockout mice model of multidrug resistance protein 2 gene MDR2 that lack P-glycoprotein in the canalicular membrane which leads to bile acids and phospholipids accumulation resulted to inflammation and rather HCC [155], also in chemically induced liver cancer with diethylnitrosamine DEN (mice lacking IkappaB kinase beta IKKbeta) exhibited an increase hepatocarcinogenesis [156]. Study identified involvement of phosphatidylinositol pathway in PBC that interplay with innate and acquired immunity [85,157]. The AKT and ERK1/2 signaling pathway activated by CBAs via SIPR2 hepatocytes and cholangiocarcinoma cells [158]. Identified a kinetic-based regulatory mechanism that determine between methyl and sulfur when limitedly available, it is the rate of cytosolic Fenton reactions that dictate nucleotide and RNA synthesis rate in cancer cell division [134]. Of which, Bacteroides fragilis correlate with GUDCA and TUDCA elevated level via methionine and folate modification inhibition. Thus, study revealed its beneficial effect dependent on bile salt hydrolase inhibition activities in B. fragilis via Amp-activated protein kinase-independent mechanism (insulin resistance and glucose tolerance) [159]. Consistent with other study beneficial effect of fexeramine modulate gut microbiota that induced acetatifactor and bacteroides with increase in bile salt hydrolase BSH thereby produces LCD from CDCA and UDCA through 7α- dehydroxylase and 7β-dehydroxylase activity [160]. In a different way, FXR regulate host metabolism and shape the gut microbiota by decrease FXR agonist BAs or increase FXR antagonist BAs in FXR signaling by large mass of BAs, importantly a positive feedback mechanism for regulating BA synthesis revealed [161]. Remarkably, study has reported mechanism that uses bile acids from gut microbiome as link to regulate chemokine which controls hepatic NKT cell accumulation, tumor growth inhibition (Figure 7) [162].

Figure 7: Growth factor (IGF, EGF, TGF alpha, PDGF, FGF).

Growth factors involve in regulation of biological processes. The different pathways involved in cancer. RAS/MAPK, PBK/ AKT associated with cancer both in cellular and intercellular differentiation. WNT-β-catenin and Hedgehog pathways disruption play roles in stem cell apoptosis. Translocation of Β-catenin regulate c-myc, cyclin-D and survivin from cell membrane to nucleus, of note act as coactivator of β-catenin enhancer associated with E-cadherin in the family transcription TCF/LEF [163]. At adherens junction, β-catenin associate with E-cadherin thereby link to actin cytoskeleton. In WNT pathway, β-catenin proposed degradation by phosphorylation, of which mutation will allow its escape to nucleus. Thus, enhanced target genes transcription that leads to cancer via different ways (inactivation or alteration) [164]. In hedgehog, blockade of PTC and SMO effect occur upon HH ligand that leads to the GLi to target gene. Frizzled activation via WNT pathway block β-catenin phosphorylation that leads to degradation of GSK-2β, APC and akin scaffold protein Akin. In TKR-dependent pathways, ligand bind to a growth factor triggers tyrosine kinase activity and transduction initiation. RAS/MAPK and ERK gene expression enhance proliferation. The two different mechanisms involved via MTOR induction through 5ʹTOPdependent and CAP-dependent (p70S6 and 4EBP1).

TRIM cofactors genes is the new target of the liver cancer

Genome-wide association studies identify sequence variants that associates increase risk in liver disease. TRIM24, TRIM28, TRIM33 were identified in liver cancer, thus showed much larger complex between TRIM24 and TRIM33 than TRIM28 and TRIM33 [21]. In line with identified alteration in gene expression associated with tumor liver formation and loss of function in gene mutation TRIM24 and this expression level were significantly altered in tumor of 55 genes resulting in 2.1- to 392 fold upregulated and 3- to 10 fold downregulated [29]. In addition, interaction between potent DNA-binding-dependent transcription repression domains TIF1 β and not TIF1 α and γ, krȕppel-associated box domains containing zinc finger protein is corepressor [165]. TRIM family member interactions interface between various receptors such as AF-2 activating domain of nuclear receptor TIF1, mSUG1 depends on AF-2 fusion and nature of receptor. The activation factor 2 of NR mediated transcriptional activity via different mechanism [166]. TRIM24 target endogenous p53 degradation confirmed negative pathway which regulates p53 drosophila and serves as therapeutic target thereby restore tumor suppression [167]. TRIM33 acts in different pathways of TGF β receptor are by phosphorylate drosophila mothers against decapentaplegic protein SMADD 2/3 as cofactors and as a monoubiquitin ligase for SMADD 4 [168,169]. TRIM24 genes identified to deregulate germ line mutant in liver [29]. Importantly, inactivation of TRIM24 tumorigenic effect was associated with deregulation of RA signaling in HCC, acting as a repressor to retinoic acid RA signaling and tumorigenesis in hepatocytes [29,38]. A subset of endogenous KRAB/ZNFs upregulate pluripotent stem cell [26]. HCC developments were significantly suppressed which observed in single retinoic acid deletion of alpha-receptor in TRIM24 null mice [29]. Notably, RARA expresses alteration of oncogenic activities correlate with dysregulation of retinoic acid signaling pathways in the postnatal developing liver [29]. Retinoic Acids (RA) a metabolite of vitamin A, it controls function of vitamin A that requires for growth, development and exert it biological function through binding and activating nuclear RA receptors RAR such as RARα, β, γ isotypes of which its impairment have been associated in various cancers [38]. Whereas, chemically induced transcription to prevent liver cancer by diethylnitrosamine DEN that accelerated in liver development, confirming TRIM24 as a tumor suppressor [38], recognized to regulate diverse cellular activity such as DNA repair, mitogenic signaling, protein ubiquitination and degradation [170]. TRIM33 function via inhibition of TGF-β signaling and execute their function in different way such as by inducing apoptosis in HCC cells and cytostasis [171,172], furthermore, induced different signal in other mediate liver tumor progression and invasion [173]. However, treatment improves apoptosis induce by different pro-apoptotic stimuli in TGF-β, highly express in liver tumor and cytokines [174]. Genetic alteration has been report of different pathways that implicated in liver cancer, revealed by genome wide allele-type studies and molecular cytogenetic analysis that inactivate p53 tumor suppressor gene associate to aflatoxin B1 exposure and HBV infection of which activation of cyclin D1 disrupt of Rb pathway involve in liver tumorigenesis [175]. Wnt-β-catenin pathway activated via CTNNB1/β-catenin mutation [40,41], AXIN1 also RB1 inactivation and IGF2R pathways via RB1, P16, IGF2Rs [40,175], described the structural and functional alteration of hepatocarcinogenesis that signaling pathways has been implicated [39]. It is essential to know that TRIM 33 and TRIM24 can interact via RBCC domain of KAP-1 using purified component, showed that KAP-1-RBCC oligomerization necessary for KRAB domain binding stating three of TRIM component act together in KRAB recognition [32,176,177]. However, the existence of TRIM28 and TRIM33 in same complex with TRIM24 was shown, as TRIM33 and TRIM24 most abundant and TRIM 28 least abundant [21,177]. Suggest that TRIM24 repress RA while TRIM33 modulate TGF-β signaling pathway [21].

TRIM24 overexpression were associated with HCC onset and progression, whereas knockdown TRIM24 showed an increases the p53, Bax, Caspase-8 protein levels, on the hand decreases Cyclin D1, CDK4, Bcl-2, survivin suggesting role TRIM24 play HCC pathogenesis [115]. TRIM24 can promote progression of tumor, recent study confirmed association with increased levels of TRIM24 protein in breast cancer and progression of prostate cancer due to overexpression of TRIM24 [178], other study report that poor prognosis and metastasis found in HCC may have been promoted by TRIM33 [179]. Moreover, TRIM24 interact with TRIM28, TRIM33 formed regulatory complex that suppressed in HCC and TRIM24^-/- develop tumor in the liver [21,38]. Thus, genetics of knockout mice showed an increase of HCC that are significant implicated RARA in liver specific cancer [38]. TRIM24 knockout expression of apoptosis-related proteins observed in Caspase-8, Bcl-2, Bax, p53, Survivin, that upregulated in Bax, Caspase-8, p53 TRIM24 depletion, downregulated Survivin, Bcl-2 [21]. Consistent in the role TRIM24 play in proliferation and apoptosis as directly ubiquitinated p53 negatively regulate protein levels in breast cancer [167]. Correspondingly, in suppression of cell apoptosis, promote differentiation of hESCs via ubiquitination p53 [180].

Participation of p53 (tumor suppressor) mutation in different biological processes was established, of note showed its important role in HCC development [181]. Inhibition effect of TRIM member family significantly promoted in HCC development and progression through regulation of p53 pathway downstream signals [182], which inhibited colony formation in vivo by deceased tumor growth [182,183]. Remarkably, liver specific deletion of p53 in cancer was confirmed (loss of p53) independent of transforming growth factor beta TGF-β [184]. Additionally, TRIM58 function as tumor-suppressor gene via inhibiting cancer cell invasion through EMT, MMP activation, observed in highly overexpressed inhibition of colorectal cancer CRC cell invasion and lesser effect on proliferation and migration [185]. Furthermore, study showed significant in reduction of expression which down regulated in liver malignancy DRLM at deleted region termed class 11 tumor suppressors in HCC [43,186]. It has been reported also, that PNPLA3 was ending, variant rs738409, p.I148M associate with hepatic glyceride level, cirrhosis, NASH increase [90,187,188], and TM6SF2 encoding membrane 6 superfamily member 2 associate with NAFLD [91,119]. Abul-husn et al. identified new gene variants includes SLG39A12 encoding solute carrier family 39 member 12, GOT1 and GPT, both encode ALT and AST respectively. These have previously identified by other studies, also variant rs7261567: TA (HSD17B13) encode hepatic lipid droplet protein, associates with ALT and AST level reduction (p꞊4.2×10^-12 and p꞊6.2×10^-10) in NASH [94]. Another studies reported identification of PNPLA3 [90], TM6SF2 [91], SAMM50 [92], ERLIN1 association in liver disease [93].

Trim cofactors gene can regulate liver cancer via gut microbiome

Gut bacteria can regulate liver immune responses through both primary and metastasis cancer of which gut microbiome composition affected by different factors (genetics) stated below. First, let us look into gut as a microbial inhabitant that interacts with immune system influence innate and adaptive immune function. Emerging studies referred gut among the major sites of microbial inhabitant in human body, it harbor diverse microbes play roles in well-being of their host. The diversity of human microbiome composition and microbes in healthy and disease is complex [189]. The human gut microbiome composition can affect by different factors like genetic, environment such as dietary, drugs and intestinal motility [190] and physiology [191]. Genetic susceptible to disease influence on the gut microbiome varies among human distinct in genus and species [190]. The individual connection and human associated inhabitants between microbes [192], immune function [193] and metabolite [194], which influence the development of microbes starting from birth (infant) to disease state [195-197]. These have established by different experimental, computational tool and technologies that has stored in database by different research project [13,198,199]. Although mechanism are less known but the early interaction of immune system to commensal believed to occur through the passage of birth canal and colostrum of which certain factor in breast milk like immunoglobulin A, immune cells-cytokines, metabolites living microbes in breast milk involved [157,196,200]. However, association of specific diseases to the taxa should be intense [190]. Microbiota diversity of uncharacterized gene and species based on large scale microbiome profiling projects [198,199,201-203], and rare variant of little effect that difficult to identify by genetic means [13], but systematic identification using high-throughput sequencing and human genome [204]. Emphasizing on privacy protection based on the control or handling of microbiome nature of these high resolutions tracking the microbial variables in future is indeed terrifying [205]. The human genetic variant studies associated with different human diseases [6,205], have established such as in obesity [206-208]. Asthma [209-211], inflammatory bowel diseases [212], hypertension, [213] diabetes [214,215] alcoholic liver disease [216], Parkinson [217], and liver [218] through mRNA and regulatory sequence of difference in translational variability [217,219]. The microbiome, genetic susceptibility, epigenetics regulation, environmental factors involve in complex interaction in development and progression of diseases. Though genetic susceptibility usually demand as a basic etiology for disease condition, in the case of fibrosis with a classic Mendelian inheritance of which microbiome play roles in but might not be the only cause such as in Parkinson [217] and IBD [220].

The gut microbiome has intimate interaction with host immune system can influence by adaptive and innate immune functions [221], which include neutrophils, DC, NKT, development of Tcell subtypes associate to a particular microbiome [222], of which adaptive immune response involve in B and T cell activation. Interaction between gut, liver, immune system metabolisms thus showed microbiome involvement. Study identified gram negative bacterial (LPS) as a triggering factors situated at blood stream from gut at the early development of metabolic endotoxemia diseases of which insulin resistance associate with a low-grade inflammation [223]. The gut wall bacterial contain molecule LPS and when altered it becomes leaky whereby LPS goes into the blood stream, excessively dysregulates the inflammatory tone and triggers glucose metabolism. Noteworthily, gut microbiome function and bacterial composition change associated with dysbiosis result in an increase of oxidative stress thereby motivate a chronic inflammatory response [224], indicated that inflammatory response has connection between immune system and gut microbiome. Study identify organisms that have ability to exacerbate inflammation with a reduction among members of its microbial community known to produce short chain fatty acid [225], whereas gut epithelium deficiency fatty acid: butyrate acids have ability to raise an inflammatory responses [226].

The role diet and chemical play in disease management need to put under consideration. The metabolism of microbiome can modified by the host genetic, environmental factor based on dietary consumption and most changes are reversible although microbiota abundance depend on diet history [206,227-229], Shaping individual microbiome associated with complex polygenic traits that affect microbiota composition in three ways [228], and change in BAs. BA increase glucose uptake was confirmed and cold acclimation have effect on skeletal muscle insulin sensitivity of T2DM patients which lead to glucose transporter type 4 GLU4 enhancement [230], GLU4 allow facilitated diffusion of glucose down into muscle and fats cells which phosphorylated by glucokinase in the liver. Cold induction of thermogenesis is a mechanism to maintain body temperature in cold exposure in animal that has gained interest in BAT discovery. In addition, cold exposure mice reduced obesity, improve insulin sensitivity, energy expenditure [231], promote thermogenesis cold exposed proposes beneficial metabolic effect that mediated direct by BAs via TGRS or indirectly by changes in gut microbiome composition via alternative pathway [232]. The amount of energy expenditure activated by dietary induced thermogenesis DIT produces heat by brown adipose tissue BAT in cold exposure, BAT induction increases energy expenditure which associates with lean phenotype mice also mediate BA metabolism via FXR and AMPK signaling and bring about changes in gut microbiota [233]. Inflammation signaling and glucose metabolism modify by antibiotic induce in gut microbiota [234], and in early life murine metabolic homeostasis alteration [235], growth and energy homeostasis [236].

TRIM family proteins established its role in innate immunity, differentiation, migration, proliferation, apoptosis, tumor development and progression [237,238]. Importantly, it is involved in biological processes [237,239-241] TRIM24 (potent liver specific tumor suppressor) family proteins confirmed to take part in p53 regulation while TRIM28 in p53 inactivation of note are largely expresses in cancer [238]. Study identified role of TRIM28 (KAP1) as a cofactor and regulator of myoblast differentiation MyoD (controller of myogenesis) function of which phosphorylation of KAP1 were mediated by MSK1 thereby releases corepressor from the scaffold [48], thus involved in recognition and repair of DNA by serine 473 and 824 (cellular DNA damage response) [34]. TIF1s interact with transcriptional silencing domain of drosophila (KAPI), of which TIF1 gene family involved and influence in the initiation of transcription [36]. Likewise trim28 interacts with KOX1/ZNF10 that represses transcription [242].

The role of enzymatic reactions by BAs synthesized in liver via different BA synthesis pathways, encode CYP7B1 and CYP27A1 gene followed by 25 hydroxycholesterol 7-α hydroxylase gene [243]. Worthmann et al. identified CYP7B1 induction as a key BA gene increases synthesis and energy expenditure [244], which BAs identify as an important metabolic effector based on BAT activation cholesterol and energy metabolism by the host. The both conjugated with taurine and glycine, activate the transcription factor and nuclear hormone factor FXR via fibroblast growth factor FGF 15 and 19, thereby generate endocrine negative feedback signal to the liver and other effect such as glucose metabolism in T2DM, fatty acids and cholesterol [245]. The conversion of hydrophobic CDCA to hydrophilic differs between rodents and human in BA metabolism [246]. Study observes lower hepatic CYP7B1 gene expression in obese and T2D patient, attribution to the CYP8B1 induction, inhibition of CYP8B1 knockout mice altered by BA composition repress hepatic de novo lipogenesis DNL and gut microbiota homeostasis, DNL that account between 10-30% hepatic fat accumulation of triglyceride in the liver of NASH and NAFLD [247,248]. Although, without conclusion to the combination effect of BA synthesis on the microbiome composition of both human and mice connection to BAT activation. The study of combination effect on microbiome composition suggested that BAT might have caused diversion in BA synthesis, observed in both mice and human [246]. In identification of BA, study indicated location of increase brown adipose tissue iBAT that upregulated energy expenditure, BA activate by BAT in human [249], and activates FXR and TGRS to regulate thermogenesis [250], promote energy expenditure and inhibit FXR activity of AMPK. Contrast to other study that AMPK activated [251], therefore increases expression of phosphorylated AMPK in the liver [252]. For instance, in absence of bile acids receptors FXR liver tumors developed in knockout FXR mice, indicating roles FXR play in BA regulation [253,254].

More so the activation of FXR in the liver controlled BA synthesis via negative feedback by reduction of secondary BA muricholic acid MCA (FXR antagonist) [255], also in gallbladder [256] of which state that gut microbiota play roles in BA metabolisms and regulation in liver [255].

Bile acid produces in liver from cholesterol, secrete by hepatocyte into bile canaliculi stored in gall bladder. Bile is being flow to duodenum after ingestion of food, help in solubility and digestion of lipid which absorb by passive diffusion, transport from terminal ileum back to liver via portal vein [257-259]. Bile involve in development of liver cancer, help to break down fats. Gut microbiome use BA shape liver immunity. The bile that secretes in liver altered by intestinal bacterial overgrowth, systemic infection which obstruct bile flow promotes in gut microbiota [260], thus leads to conversion of primary to secondary bile acids. Notable negative feedback regulation of BA synthesis disrupted mutant mice thereby cause alteration that leads to liver disease [261]. The metabolic pathways in which bile acid synthesize in liver, thus taurine and glycine are primary bile acid (CA - TCA, GCA and CDCA: TCDCA, GCDCA) conjugate as bile salts (7-α dehydroxylase) mediate cholesterol oxidation by the enzyme (cholesterol 7-α dehydroxylase) which downregulate cholic acid. The bile acids biosynthesis is downregulated by suppression of expressed CYP7A1 via c-Jun N-terminal kinase dependent pathway and upregulate by a protein FGF-19 secrete by the ileal enterocyte and mediates sodium dependent BA transporter (apical) which uptakes across ileal enterocytes [258]. In the intestine, bacteria transform this BA into secondary BA (deoxycholic ac DCA, LCA) that absorb into blood stream, returned to liver via enterohepatic circulation and finally enter liver acinus [159,262]. Cholangiocarcinoma have been significantly linked to liver diseases, thus evidence of an increase found in cirrhosis patient and associates to intrahepatic cholangiocarcinogenesis [123,263]. JTE-013, a potent selective antagonist S1PR2 bind to human, rats receptor, inhibited TCA, SIP-induce ERK1/2 and AKT activation in cholangiocyte, that reverses inhibition of SIP on invasion and migration of B16 melanoma cells. This study reported that JTE-013 specific shRNA of S1PR2 and chemical inhibitor of ERK1/2 and AKT inhibited TCA and SIP cell proliferation and migration in cholangiocytes mice [264].

Bile acid is the key regulator of glucose, lipid metabolism and energy homeostasis via membrane and nuclear hormone receptors by FXR (OCA) that have tested in primary biliary cirrhosis patient who does not respond to ursodeoxycholic acid [258,265]. Indeed FXR have molecular link between BA and plasma lipid play role in control of triglycerides [266,267], and cholesterol metabolism [268]. Remarkably, patients responded to UDCA therapy showed normalize survival rate when given at early stage of PBC [269]. Importantly, farnesoid X receptor agonist (OCA) decreased hepatic steatosis, insulin sensitivity in T2D and NAFLD [120,257,270]. In addition, inhibition of lipogenesis due to FXR activation, function as the suppression of CYP7A1 in human elevated level of deconjugated TUDCA and GUDCA that suppressed by decrease of Bacteroides fragilis bile salt hydrolase BSH [159]. Study report that FX nuclear receptors signaling affect lipid metabolism in the liver, which can change with FX nuclear receptors ligands [8]. As ligands for GPCRs- TGR5 (GPBAR1 gene), membrane bile acid receptor locates on chromosome position 2q35 in humans, encoding 330 amino acids with 993 base pairs open reading frame, TGR5 mRNA expression detected at high level in various organs like small intestine, liver, stomach, lungs [257,271]. Given that change in protein expression involve in production, secretion and recirculation of BA can alter BA signaling, transport and modulate expression and activity [159,257]. Noting that the nuclear receptors FXR, transcription factor modulate production and BAs metabolism in liver. For instance, the growth of Bacteroides fragilis inhibited by metformin via folate modification, methionine metabolism and intestinal FXR signaling via gut microbiota modulation [159], In addition, activation of FXR prevented in vivo induced synthesis oxidative stress enzymes, proteinuria and glomerulosclerosis in diabetic kidney disease using FXR modulation [270]. TGR5 is not for bile alone but various selective synthetic agonists such as 6EMCA, 4-benzofuranyloxynicotinamide derivative to regulate different signaling pathway like NF-kB [272,273]. On the other hand AKT, ERK metabolic regulator involve in glucose metabolism, bile acid and energy homeostasis, even in inflammatory response, cancer and liver regeneration [274,275], which takes part in physiology of liver and gall bladder [257]. Importantly, TGR5 activation of bile acids increase GLP1 and insulin secretion, in line with, FXR inhibition through GUDCA elevates serum active GLP1 level (Figure 8) [159].

Figure 8: Gut microbiota influences host metabolism via modulation of metabolites including LPS, BA, Immune cells.

(A) Liver exposed to gut bacterial metabolites through blood via portal vein. Liver produce cholesterol through hepatocytes in the liver synthesis and transform primary into secondary BAs by enzyme hydrolase, 7α-/β-dehydration in intestine [276]. Bacteria in the gut mediate the metabolism of bile acid and regulate liver cancer through NKT-cells. Microbiota modulates the expression of several enzymes via bile salt hydrolase. Hepatocytes produced primary bile acids that transported into the duodenum. Some bile acids reabsorbed and other remaining convert from primary bile acid to secondary bile acid as result intestinal bacterial action in the colon. Secondary bile acid inhibit the activation of Liver sinusoidal endothelial cell LSEC while primary bile acid promote protein chemokine ligand 16 CXCL16 production by LSEC, an increase expression of CXCL16 will recruit NKT cells [162]. Of note that NKT cells produce IFN-γ, ILs thus has antitumor effect. After travel through duodenum to colon, most of the BA will recycled. It will be absorb at terminal ileum and recycled through enterohepatic circulation. Primary BA stimulates the expression of CXCL16 that interact with the CXCR6 receptor. Endothelial barrier consist of LSEC that regulate the hepatic immune homeostasis. Nuclear receptors and membrane bound receptors regulate metabolic immune related processes [277].

(B) Epithelial barrier bound across tight junction. The innate and adaptive immune cells maintain homeostasis at steady state. Alteration allows luminal microbiota to trigger unlimited inflammatory response. Factors contribute to disruption of tight junction are inflammatory cytokines secreted from activated immune cells in lamina propria. LPS translocation occurs through intercellular space to systemic circulation. LPS and bacterial reach the liver via portal vein and metabolize or acts as ligand of PRR such as TLR. Bacterial LPS acts as a triggering factor [223].

Trim cofactor genes can regulate liver cancer immune cells

Human body comprises of defense system that made up of entire organs and vessel system such as lymph vessel and individual cells and proteins. Immune system is system comprises specialized cells, organs that protects against organisms or invaders called antigens and respond immediately. They classified as innate and adaptive immune system [278], contain humoral, cellular component in each immune response that recruit, activate immune effector cells which are the resident immune cells (granulocytes: basophils, eosinophil, macrophages- recycling dead cells like RBC, fibroblasts, mast cells [279] releases inflammatory chemical like histamine, dendritic cells (antigen presenting cell APC). Natural killer cell (innate and adaptive) cause apoptosis do not release signal leads to immune activation and inflammation. Leucocytes like monocytes develop to macrophage and neutrophils that possess surface receptors as PRR (TLRs, NLRs) [280]. Of note loss of negative regulation of TLR signaling was associated with the pathogenesis of autoimmune diseases and inflammation as Atg16L1 negatively regulate TRIFdependent pathways cause casepase-1 activation [281].

Liver is exposing to pathogen or microbe-associated molecular patterns through PRR such as TLR and NLR. Immune responses (innate) are triggered by TLR play role in innate immune responses and other PRR by viral [17], fungal and bacterial infections. The loss of negative regulation of TLR signaling associated with autoimmune and inflammatory pathogenesis, thus play role in host defense and diseases [281,282]. The involvement of five adaptor protein by TLR signaling, SARM negatively regulate TRIF induce IFNβ for activation of interferon IRF3 family [283]. Thus bind to one -two classes of molecules such as PAMPs (β-glucan of fungi, endotoxin or LPS of gram-negative and LTA of gram positive bacteria) [284,285]. Of note, immune recognizes P/MAMPs via PRR as stated above. PAMP with some endogenous molecules play roles in facilitating adaptive immunity against infected microbes thereby activated innate immune via TLRs and PRR as an adjuvant [281]. Study identifies LPS and bacterial DNA as a prototype of P/MAMPs [286]. In established model of two strain mice (C57BL/10ScCr and C3H/HeJ) unresponsive to LPS highly resistant to LPS induced shock by TLR4-deficient mice [287]. The damage associated molecular pattern DAMPs [278,288] either repair, stop, invade or remove foreign particles and host debris by phagocytosis to the infection site through chemical mediators production like chemokine and cytokines [289], tumor necrosis factors TNF-α, IL-1, 6 and IFN-Y can lead to cancer when activated. Of note, involve in inflammatory changes that occur during obesity development thus affect adipose tissue inflammation [290]. It have been found that SIBO increase intestinal permeability, alter by colonic microbiota composition which releases pro-inflammatory cytokines LPS to reach liver via portal vein to systemic circulation [291]. The innate signaling regulation response also triggered by toll-like receptors TLR signaling lipopolysaccharide LPS-induced transcriptional regulation of inflammatory responses [280,289]. In addition, the innate immune cells can activated via PRR by immunogenic cell death ICD induce by injury, stress and chemotherapeutic agents in cancer cells [288]. As type 1 IFN production was impairment resulted in the loss of TLR signaling [292]. In recognition of microorganism by PRR triggers activation of antimicrobial defense, stimulates adaptive immune responses [293]. Disruption of intestinal barrier leading to increase permeability, which influences the bacterial metabolite and PAMPs/MAMPs that liver are expose to. Of note liver feeds back to the intestine through bile acid secretion and mediators. Immunoglobulin A produced by B-cells, of which it plays important function in host microbiota homeostasis regulation [294].

Adaptive immune system consist highly specialized system (T and B) cells [278,293]. The process that eliminate or prevent pathogenic growth, which are being triggered when pathogens invade innate immune system and generate a threshold level of an antigens and signals [281,293], it start to work after innate immune system is activated, dendritic cells thereby initiating antigen-specific immunity [295]. The mechanism of adaptive immune system activate via three pathways (classical, lectin and alternative) [279]. PRR interact both exogenous and endogenous ligand via APC integrating signal with cellular interaction to generate diverse responses [284]. This provide the body ability to recognize and remember by these specific pathogen (APC) such as dendritic cells, also by macrophage via phagocytosis which travel to lymph node- and bound MHC class II and MHC class I receptors APC. These correspond to dendritic cell macropinocytosis of antigens that identified [284,296]. The monocytes derived-dendritic cells MDDC as rottlerin inhibitor of macropinocytosis [297], presents to immature helper and cytotoxic T cell through binds to MHC class II (T_helper CD4⁺ cell with four subsets- Th1, Th2, Th17, Treg) or MHC class I (CTL). Resulted in upregulation of MHC II, cytokines, chemokine and T cells via antigen receptors [295], and T cells lymphocytes matures and proliferate, the helper T cells activate B cells (expresses in two ways) which will later proliferate and produce antibodies (immunoglobulin Ig- IgM, IgD, IgG, IgA, IgE) specific for antigen [298]. On the other hand cytotoxic T cells destroys pathogens presented by APCs, finally T and B cells (lymphocytes) that activated become memory cells (passive or active) as memory T and B cells. More so, over 50% B-cell from HCC tumor activates showed high reduction FcyRII [299], thus established inflammation liver disease CD8⁺ T cells accumulation. In correlation with tumor-derived CD8⁺ T- cells dysfunction that have ability for proinflammatory TNF-α, IFN-γ production, cytotoxic GzB and perforin [299]. Furthermore, T-cell induced mucosal damage by perforin via combined effect of different pathways of cytotoxicity like IFN-γ, TNF-α, perforin and Fas/FasL Fas ligand (play role in regulation of immune system and cancer progression) [300], noting that perforin contribute to apoptosis through perforin pores causing granzyme introduction to the target cells. Interestingly, study reveals tumor cells release autophagosome TRAP induces B cell differentiation in IL-10 produces B cells and suppress T- lymphocytes activity [301], ameliorate neutrophil apoptosis in cell lines and tumor cells through macropinocytosis via caspase-4 and reactive oxygen species ROS generation, thereby inhibited CD8⁺ and CD4⁺ T proliferation [302], which could be employ as immunotherapy. Suppressed tumor-induce immune reduction in cancer patients, consistently in other study ROS which produced by NADPH oxidase play role in neutrophil cell death mechanism, through pro-apoptotic Bcl-2 and caspase activates either by necrosis or apoptosis [303]. Recent study revealed that TRIM33 (lineage dependency) associated with two lineage- specific enhancer PU.1 transcription factor TF (PU.1 TF), which negatively antagonize its function by same element that being recruited [51]. Among B cell acute lymphoblastic leukemia BALL cell analysis of gene expression, Bim and Atp1b3 upregulated in TRIM33 reduction [51]. In line with study, that Bim play role in B-lymphocytes deletion and Bcl mediated apoptosis because of loss Bim, which inhibit the deletion of autoreactive B cell [304].

Adaptive immunity of IgA⁺ cells prevents cancer envelopment; suppress liver cytotoxin CD8⁺ T lymphocytes CTL activation in HCC and Mice [299,305]. Study of cancer immunoediting mechanism involves the use of combine immunotherapy that shaping tumor fate in three phases, increased therapeutic index [306], of which mechanism dependent of NK cells and IFNγ [307]. A combination of antitumor and CpG–a TLR9 agonist trigger activation of the systemic antitumor immune response remarkably shows a therapeutic memory response in mice expression of OX40 and CTLA-4 immune cells upon tumor recognition antigens that inhibited by tumor-specific Tregs via upregulation of TLR9 [308]. Furthermore, the combination of anti-OX40 AND CTLA-4 with TEA therapy enhanced better responses [309], which maintained a constant internal environment for homeostasis clearance mechanism of the host pattern recognition [284]. Studies identify human subset and type II NKT_TFH cell regulate B-cell contrary to gaucher disease, metabolic lipid disorders via glucosphingolipid mediated pathways and dysregulation of humoral immunity [310]. Type 1 IFN activation upregulate PD-1-PD-L1 signaling axis in tumor tissues by NK and T-cells indicates its beneficial therapy PD- 1-PD-L1 blockade [311]. Natural killer, NKT and Dendritic cells may be responsible for innate immune response limitation (impaired) and degeneration in HCV through various pathways [312], thereby generate diverse responses from exogenous and endogenous ligand by APC with cellular interaction responses [284]. IFN-γ can induce autophagy by different proteins, establishing its role in autophagosome formation [239]. TRIM24 negatively regulate tumor suppressor p53 levels established TRIM24-p53 links [167]. TRIM33 act as tumor suppressor in human CMML and mice thus play role in preventing the onset development of CMML [55]. Suggesting TIF1G regulate epigenetically tumor suppressor gene in hematopoietic cell. Studies reported relationship between TRIM family protein and autophagy. Based on recent studies that TRIM proteins interaction with p53 protein [313]. Another study reported autophagy-related Atg proteins involved in autophagosome formation [314]. In addition, p62 mediate Nrf2 activation because of ubiquitinated protein accumulation in damaged tissues [315]. Autophagy referred as a natural occurring cyto-protective mechanism degradation that play crucial roles in induction both preventive and therapy of healthy and tumors cells [316]. Thus, show alteration of HIV infection through the process of autophagy [317]. Those induce by chemotherapy, autophagy by starvation, growth factor deprivation and hypoxia [318]. Programmed cell death or apoptosis are two different ways by which cells respond to stress [319], that can inhibited by antibiotics, of which lgG (IgG1 and IgG3) is most used in cancer immunochemotherapy [298]. The approach described for microautophagy and macroautophagy of which inhibitors that affect microautophagy steps not impair delivery of peroxisome to vacuole via macroautophagy [320]. Besides autophagy identify as promising target in cancer therapy, of which Beclin1- silenced B16F10 cells that secret TRAP have little LC3- II that correlates with decrease ability to induced PD-L1 and IL-10 [321]. Accordingly, glucoseinduced micropexophagy in two distinct pathways [322], more so autophagy-related three different pathways can also induce Atg proteins: starvation-induced pathways, Cvt pathways, pexophagy (autophagic degradation pathways peroxisomes in yeast cells), all to core machinery for membrane formation [314,321]. Furthermore, autophagosome modulate effects of immune cell function and tumor progression [301]. On which autophagy a normal protective survival mechanism for cells that undergo different ways of stress and formations in three major ways [309], started with the formation of autophagosome thereby releases extracellular fluid by inhibition of proteasomes or protein oxidation increase or accumulation of misfolded proteins of vitamin E analog on stress induction [301]. A semi synthetic vitamin E derivative (α-TEA) induced tumor cells apoptosis and autophagy thereby improves cross presentation tumor antigen on lung immune and murine mammary tumor cells [309]. TRIM family protein directly or indirectly involved in regulation of autophagy, carcinogenesis and immunity, it regulate immune responses through innate immune signaling such as NFKB signaling and IFN signaling [313].

Tripartite motif containing proteins play broad range of function on inflammation [323]. Thus, exert its regulatory role in various biological processes like differentiation, growth, apoptosis, carcinogenesis and antiviral immunity [237-241]. These roles were observed of TRIM8 in inflammation, cancer regulation expressed pro-inflammatory cytokine and IFN related transcription factor [324]. Furthermore, negatively regulate the interferon promoter activity and in different way regulate the transcription of pro-inflammatory factors in overexpressed EcTRIM13 [325]. Investigations supported by some other studies showed those liver progenitor cells activated when mature hepatocyte compartment are damaged due to chronic inflammation or toxic injury [326]. For instance, of cells levels that respond to carcinogenesis in the hepatic lineage such as mature hepatocyte, ductular progenitor cell and putative periductular stem cell [327]. Of those, different cell signal involve in this process such as immune cell, growth factor [328,329], cytokines which are produced by various immune cells like macrophage, B and T lymphocytes, mast cell act through receptors. On the bases of cytokines network initiation through the binding of TNF-TNFR1type 1, activated NF-KB in NPC to produce IL-6, STAT3 activation in hepatocyte [330]. Given that, oval cells (hepatic stem cells) significantly unchanged impaired TNF type 2 knockout mice noting IL-6 reduction suggest TNF signaling contributed to this effect [329]. However, study emphasize that it originated from HSC of which migrate to liver and differentiate into hepatocyte [326,331]. Furthermore, oval cells expresses high level of Sca-1, CD35 and CD45 [331], Correspondingly supported by another study that the fusion between hepatocytes and transplanted hematopoietic cells possibly mechanism by which hepatocytes are being generated [332]. Progenitor cells said to be the progeny of stem cells and when isolated from certain organs depends on ability to differentiate into different TSP (plasticity) such as liver (portal space-bile duct cells and parenchyma-hepatocytes) [326]. Importantly, showed evidence of cytokines pathways activated between Kupffer cell and hepatocyte in liver regeneration and metabolic pathways [330]. More so, nuclear factor-kappa β [333], STAT3 [334], C/EBPβ [335], and transcription factor plays role in liver regeneration in sense that it can extend signal by activating various genes [336].

Tripartite motif protein family contain ring finger domain also involved in several of cellular functions. Study observed regulatory innate immune response through modulation of PRR signaling pathways [17]. Cells possess surface receptors as PRR which bind to PAMP like protein, lipoprotein, lipids, nucleic acids [292]. Moreover, various signaling pathway involve in NF-k B, AP-1, IRF protein activation, PAMP recognition by TLR dimers has been identified and characterized [281], besides its role in host defense was established [17]. Furthermore, TRIM family proteins directly interact with cellular proteins as a combined effect or single thereby modulate signaling pathways that triggers engagement of PRR. The expression pro-inflammatory responses (cytokine) affect IFNs (type 1 and 11) by downstream regulation, also promote adaptive immune responses [19].

NK and NKT cells

Liver is immunological organ that are circulate mainly by immune cells and expose to gut microbiota via portal vein. The liver diseases are usually associates with altered gut bacterial composition. Gut commensal bacterial is an important regulator of antitumor immunity, reported that NKT cells is a regulator of autoimmune responses [337]. According to one study that alteration of gut commensal bacterial induces liver selective antitumor effect thereby increases hepatic CXCR6⁺ NKT cell, NKT cells accumulation were regulate through expression of hepatic CXCL16, a ligand for CXCR6, as primary bile acids increases expression of CXCL16 while secondary bile acids reverses it [162].

Natural killer cell is an effector of innate immune system, serves as a natural regulator to adaptive immune responses [338]. They have features both innate and adaptive immunity that is subset of lymphocytes in peripheral blood (lipid), although do not expresses membrane receptors that distinguish B and T cell lineage, they lack antigen-binding receptor, memory and immunologic specificity [339]. NK cells produces in high amount interferon-gamma IFN-γ that are used to fight viral infections [104], consistently, elevated IFN-γ production upon antigen stimulation [162], that have ability to kill tumor cells in interactions between ligands of the tumor cells and various receptors on NK cells, releases cytotoxic granules of the NK cells which produces inflammatory cytokine [340]. NK cells express activating and inhibiting receptors. While activating receptors and associated with signal transducing molecules [341].

PRR pattern recognition receptors molecules interact with both endogenous and exogenous ligand by APC (innate- macrophage and dendritic cells) and able to activate adaptive immune response (T- and B-lymphocyte) which plays dual role in host defense and normal tissue function [284]. Showing self-structures on normal, impaired, stressed and transformed cell of immune recognition mediated by NK and γδT cells involve in restriction of non-classic MHC class IB molecules [284]. The role LrNK cell play in T-cell immunity regulation were established mechanism of immune tolerance in liver, report showed that inhibition of hepatic T-cell function by LrNK CELLS caused impaired viral clearance via PD-1- PD-LI axis [342]. However, impair T-cells response induces by PD-1- PD-L1 axis showed an increase during viral infection, of which PDL1 significantly expresses on LrNK cell and PD-1 receptor increases on T-cell indicating that PD-1 blockade lead to improvement in immune response [343]. The liver residents and hepatocytes have been established for expression of CD1d [344], study had it that cholangiocytes also expresses CD1d which present antigen to NKT cells which play role in the immune system during liver disease progression thereby restricted activation [345]. NK, NKT and dendritic cells may have been responsible for innate immune response limitation (impaired) and degeneration in HCV through various pathways [312], thereby generate diverse responses from exogenous and endogenous ligand by APC with cellular interaction responses [284].

T–cells

CD4⁺ CD8⁺ is two T-cell categories base on which protein present on cell surface. CD4⁺ T-cell having four major T-cell subsets TH1, TH2, TH17, Treg refer as T-helper cells. All have different functions as TH-2 known to coordinate immune response against extracellular pathogen, TH-17 for recruiting neutrophils, TH-1 for immune response coordinating against intercellular microbes such as bacterial. They also produce, secrete molecule that alert and activate immune cell such as bacteria-ingest macrophage. Regulating T-cell Tregs function as inhibitor to the activities of other T-cells and monitoring. Also, can prevent activation of adverse immune response; maintain tolerance against body’s own cell and antigen. CD8⁺ T-cell (CTLs) known to recognize virus-infected and tumor cell removal, also stages programmed cell death (apoptosis) [319]. T-helper cells activate B-ells in two ways, which will later proliferate and produce antibodies. Antibodies are unique and fall into these various categories of immunoglobulin IgM, IgD, IgG, IgA, IgE [298].

Immunologic effect of microbiota homeostasis stimulates immunoglobulin A production, downregulate pro-inflammatory cytokine, promote anti-inflammatory cytokine, induces regulatory T- cells [291]. Study has reported that pro-inflammatory cytokines (IFN-γ) induce loss of granule thereby causes paneth cells degranulation [346], Furthermore, butyrate induce differentiation of functional colonic Treg through intrinsic epigenetic upregulate Foxp3 gene [193]. Mechanically, using single T-cell analysis of RNA-seq, TCR tracking STARTRAC identified new regulatory mechanism and therapeutic strategy to reveal connections among different T-cell subsets (IFNG⁺ T_H 1-like which IFN-γ-regulating transcription factors), CXCL13⁺ BHLHE40⁺ T_H 1-like cells enriched in microsatellite instable MSI tumors [347]. On the other hand, MHCII⁺ Lgr5⁺ ISCs of TH cells modulate ISCs renewal and differentiation in opposing ways [348]. Besides, conversion to Lgr5⁺ ISCs and ISC dedifferentiation restore function upon external stimuli and intestinal homeostasis [349,350].

The microenvironment of tumor contains various cell types that include lymphocyte, blood vessel, fibroblastic cell, inflammatory cell and bone marrow cell [351]. Cancer association with chronic inflammation involved in T-cell [139], neoantigen-specific T cell activated in cancer immunotherapy indicating highly protective [97], but suppressive element in non-transformed epithelial cells (stromal cells) in regenerating tissues of the tumor microenvironment TME mediated restriction by excluding T cells indicating effective immunotherapy [351]. Neoantigen recognized may provide effective clinical immunotherapy [97], on which TME term immune suppressive element. Effectiveness of immune-suppressive TME further verify with the increase frequency of cancer-specific T cells [97,352], whereas loss of function of MDR1 were identified in a subset of ileal CD indicating that interaction between conjugated bile acids and Teff cells can regulate intestinal immune homeostasis [353]. Of note, mucosal healing of cholestyramine CME induced in primary sclerosing cholangitis-associated with IBD [354].

B–cells

B-cells subset Breg identified plays suppressive role on the immune system. As ATM response suppression, IL-21 induces granzyme B (GrB⁺) expression by B-cells in human Breg triggered by BCR and TLR signaling pathways [355,356]. Interestingly, TRAP (tumor cellreleased autophagosome) activates TLR2-MyD88-NF-KB signaling pathways in B cell induced by Breg cells differentiation into IL-10- produce B cell by HMGB1 on intact TRAPs [301], suggesting TRAP function in the induction of immunosuppression associate with development of cancer. Noticeably, the intrahepatic abundance of B-cell at tumor margin, Breg circulation (migrate from blood into tumor) promote tumor progression in HCC which significantly correlate with tumor invasiveness and stage. Breg induce cell proliferation and directly interaction with liver tumor cells through CD40/CD154 signaling pathways [357].

Here, PD-1^high B cells identified as immunosuppressive cells induced in the microenvironment of HCC, whereas Breg cells interaction between PD-1/PD-LI induced dysfunction of T cells in different pathways either by PD-1 trigger on T- cell or regulatory B-cell produce IL-10 thereby induce effector T- cell dysfunction [358]. The immune blocker PD-1-PD-L1 interaction shows type 1 IFN activation as target for immunotherapy with high beneficial therapeutic [311]. Indeed, PD-1-PD-L1 interactions as new mechanism induce immune dysfunction during tumor progression. However, PD-1hi (Protumorigenic) B-cells trigger T-cell dysfunction and thereby cause progression of tumor via IL-10 dependent pathway [359]. B-cells FcγRII^low/- activation prohibit T-cell immunity via IL-10 signals, result establish possible pathways which induce T-cell suppress and create possible avenue for tumor progression [299], whereas, activation of T-cell caused severe impairment to the intestine and intestinal barrier disruption and apoptosis [300]. Thus, provided mechanism by which immune responses regulate gut microbiome and epithelium [346]. Recently, GUDCA (as intestinal FXR antagonist) improve metabolic dysfunction of Bacteroides fragilis-GUDCA-intestinal FXR axis via an AMPK-independent mechanism, thus increased GUDCA level by decreasing B.fragilis inhibiting intestinal FXR signaling by hepatic CYP7A1 activity in the gut [159]. Cancer epigenetic silencing (DNA methylation and histone modification) is an important tumorigenic mechanism that represses tumor production of Th1-type chemokine CXCL9 and CXCL10 and enhance clinical efficacy of cancer therapy [360]. The protumorigenic role of CXCR3⁺ as a link between proinflammatory response and immunity cancer microenvironment confirmed, proposed IL-17⁺ cells might be regulator for CXCR3⁺ B-cells trafficking to cancers [361]. Notwithstanding that, CXCR3⁺ B-cells promote recruitment and accumulation at the invading edge of HCC. B-lymphocytes plays role in cancer progression, of which TNFα-producing B-cells limit senescence-mediated fibrosis and favors HCC progression. In established model of Mdr2^-/- mice, showed distinctive B- and T- cell role of hepatic fibrogenesis, which B-Mdr2^-/- inhibited fibrosis and accumulate senescence inactivation of hepatic stellate cell Hsc [362,363]. Correspondingly, effect of immunosuppressive drug, mycophenolate mofetil MMF inhibited inosine monophosphate dehydrogenase irreversibly dependent to T and B-lymphocytes [364].

HLA cells

HeLa cells commonly been used in human cell line, which first identified since 1952 [365]. Study of identified using PCR-based assay to detect Hela that are highly specific for HeLa [366]. Various immune response genes (HLA type and polymorphisms) reported as cause of clearance in HCV [312]. The complex found in HeLa cell contained TRIM24 and TRIM 33, of note revealed in purification of TRIM24 revealed TRIM28 and TRIM 33 although are more closely related towards HPI and HDACs 1 and 11 proteins [20,21]. Recent study found genetic variant on 13 loci across HLA class 11 associated strongly with PBC [367]. Genome wide association study with help of their technology identified the risk loci as HLA confirmed being the strongest and others like IL12, IL12RB2, 17q12.21,SP1B, CTLA-4, STAT4, MMEL1, IRF5- TNPO3, immune pathway involve in T- cell differentiation, B- cell function, antigen presentation and myeloid cell differentiation in PBC [85]. Importantly, HLA associated been strongly implicated the adaptive immune system on chromosome 6 is that encode class 1 and 11 complexes, that linked HLA-type of cellular phenotype to PBC noting potential linking genetic data with clinical outcome and disease subtype . Study indicated interleukin -12 immunoregulatory signaling axis directly related to PBC pathophysiology, associated between PBC and genetic variant at HLA class 11 region, IL12, IL12A and 1L12RB2 loci [367-368]. The link between HLA allele and PBC has been reported [82-84], risk allele occur in gene associated with immune function that intersect in various immune pathways, that has been identified in GWAs study as B-cell function, T-cells differentiation, antigen presenting and myeloid cell differentiation [85]. Of note that three loci gene in TNF-α signaling pathway identified by GWA study: TNFRSFIA, DENND1B, TNFAIP2 [82,86]. Study identifies HLA-C1 ligand gene KIR2DL3 inhibitory NK cells receptors to influence HCV in liver disease [369], which is necessary for determining antiviral immunity.

Discussion

The gut microbiome has intimate interaction with host immune system influenced by innate and adaptive immune function [221], which include neutrophil, DC, NK cell. The development of T-cell subtypes associated to a particular microbiome [222], of which adaptive immune response involve in B and T-cell activation. LPS identified as a triggering factor situated at blood stream from gut at the early development of metabolic endotoxemia disease of which insulin resistance associate with low-grade inflammation [223]. Disruption to the gut wall (tight junction) resulted in alteration. The gut wall becomes leaky, LPS goes into the blood stream. Excessively decrease the inflammatory tone and trigger glucose metabolism [223]. Given that gut microbiome function and bacterial composition change associated with dysbiosis results in an increase oxidative stress thereby, motivate a chronic inflammatory response [224]. Besides, in an ability to exacerbate inflammation with a reduction produced short chain fatty acid, whereas deficiency of SCFA in the epithelium raise in inflammatory response [226]. The metabolism of microbiome can modify by the host genetic, environmental factor based on dietary consumption and most changes are reversible although microbiota abundance depends on diet history [206,227-229]. Shaping individual microbiome associated with complex polygenic traits that affect microbiota composition in three ways [228], and change in BAs. TGR5 mRNA expression detect at increase level in small intestine, liver, stomach and lungs [257,271]. The innate and adaptive immune cell activities associated to liver cancer development, given that liver exposed to P/MAMP through PRR (TLR, NLR), which were confirmed [17]. The loss of negatively regulation of TLR signaling associated with autoimmune and inflammatory pathogenesis thus plays role in host defense and diseases [281,282]. Furthermore, T-cells induced mucosal damage by perforin via combined effect of different pathways of cytotoxicity like IFN-γ, TNF-α, perforin and Fas/Fasl Fas ligand (In regulation of immune system and cancer progression) [300].

Trim family protein directly interacts with cellular proteins as a combined effect or single thereby modulate signaling pathways that triggers engagement of PRR. Expression of pro-inflammatory responses (cytokine) affects IFNs (type I and II) by downstream regulation, also promote adaptive immune responses [19]. The role of Trim family protein established in innate immunity, differentiation, migration, proliferation, apoptosis, tumor development and progression [237,238]. More especially, its involvement in biological processes such as growth factors, immune cells [237,239-241,328,329]. Trim24 involved in p53 regulation whereas Trim28 in p53 inactivation, thus highly expresses in cancer [238]. Trim33 prevent the onset development of human myelomonocytic leukemia [53]. Studies reported of relationship between Trim family proteins and autophagy [313-315].

To attend accuracy in liver disease prognosis remain challenging [122]. Genome wide investigation shows that demethylation occurs simultaneously with tumor progression and activation of transposable element via genome wide hypomethylation in HCC [133]. It has established gut microbiome and immune cell play roles in various liver disease developments. Researches have been going on using different technologies in order to unravel the link and prognosis of this disease in human. Of note, gut microbiome acted through BA metabolism to regulate liver cancer via NKT cells [162]. Despite role of BA regulation of liver cancer and modulating FXR signaling on beneficial effect on the intestinal barrier and immune function [286]. The gut microbiome use BA shape immunity of liver cancer. More so they do by altering the gut microflora thereby bring about changes between anti-tumor immunity and hepatic immune cells against tumors in liver cancer [162]. Cholestasis induce liver injury cause inflammation by alteration of BAs profiles [104]. Variant rs72613567: TA HSD17B13 associate with reduce risk of liver disease and NASH progression [94]. Alteration of Trim28-dependent transcriptional dynamics due to obesity and aging precipitate, thus leads to metabolic infection [49]. Trim28 induced by interferon to resistance of pathogen. Better understanding of PRRs (innate and adaptive immune response) needed in therapeutic and drugs development for cancer and inflammatory diseases. Since PRR signaling pathway plays role in tolerance, pathogen elimination associated in inflammatory diseases and cancer. Study suggested that OCA improved in NASH histological features indicating long-term benefit and safety of obeticholic acid OCA need further clarification [8], long-term safety, efficacy (10 mg OCA) as novel therapy in PBC patient were supported [72], whereas 25-50 mg OCA for 6 weeks was tolerated [120]. Acid dose-dependent increased incidence of pruritus with obeticholic acid, concomitant administration of obeticholic acid OCA with ursodiol or alone shows improved ALP, bilirubin level in PBC patients except pruritus no serious adverse events seen [80]. Suggesting that 10 mg of OCA to be effective dose, long-term safety, efficacy of OCA in PBC patient support 5-fold range of OCA, non-clear differences in biochemical end-point observed indicated doses to be high for trial [72]. In as much as decrease marker of liver inflammation, fibrosis with T2D and NAFLD patients, an increase insulin sensitivity observed with 25–50 mg OCA administration for 6 weeks tolerated [120]. However, UDCA being only drug approve for PBC treatment, suggested use of noninvasive marker to monitor the disease progression [258]. The time for disease development according to fibrosis stage can be included in counseling and decision of patient’s health [122]. According to one study, growth hormone may be novel target for development of liver fibrosis therapeutic [81]. More so, JTE-013 showed therapeutic target for cholestatic liver diseases [264]. The growth hormone resistance may have play role or cause onset, development of Inflammatory Cholestasis induce liver fibrosis in mice model [81]. In all these, what is the way out of this deadly disease without adverse events and relapses, whereas the role diet and chemical play in disease management need to put under consideration.

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