Hepatitis B virus‐induced hepatocellular carcinoma: functional roles of MICA variants

Abstract

Hepatitis B virus infection is a high-risk factor for hepatocellular carcinoma. The human major histocompatibility complex class I chain-related gene A (MICA) is a ligand of the NKG2D receptor that modulates the NK and T-cell-mediated immune responses and is associated with several diseases. This study determined the effects of MICA polymorphisms during HBV infection and HBV-induced HCC. We conducted a case-controlled study in a Vietnamese cohort and genotyped ten functional MICA polymorphisms including the microsatellite motif in 552 clinically classified hepatitis B virus patients and 418 healthy controls. The serum soluble MICA levels (sMICA) were correlated with MICA variants and liver enzyme levels. We demonstrated a significant contribution of MICA rs2596542G/A promoter variant and nonsynonymous substitutions MICA-129Met/Val, MICA-251Gln/Arg, MICA-175Gly/Ser, triplet repeat polymorphism and respective haplotypes with HBV-induced HCC and HBV persistence. The circulating sMICA levels in HBV patient groups were elevated significantly compared with healthy controls. A significant contribution of studied MICA variants to sMICA levels was also observed. The liver enzymes alanine amino transferase (ALT), aspartate transaminase (AST), total bilirubin and direct bilirubin were positively correlated with sMICA levels suggesting sMICA as a biomarker for liver injury. We conclude that MICA polymorphisms play a crucial role in modulating innate immune responses, tumour surveillance and regulate disease susceptibility during HBV infection.

The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma

“…In HBV-infected patients, although NK cells in peripheral blood express higher levels of the activating receptors NKp30, NKp46, and NKG2C [77], NK cell activation does not induce all effector functions to an equally high degree. During HBV infection, MICA, a ligand of the NKG2D receptor, is induced at the early stage of infection, and soluble MICA levels were associated with MICA variants that modulate the NK- and T-cell-mediated immune responses [78], which play a crucial role in HCC development in HBV-associated HCC patients. In addition, a selective defect in NK cell function during persistent HBV infection was demonstrated via several different mechanisms including induction by IL-10 and TGF-β, as well as HBV-induced up-regulation of Tim-3 expression in NK cells, which in turn suppresses NK cell functions [79,80].…”

MICAMICA-129 Met/Val Variant as Possible Biomarker of Diagnosis and Prognostic of Gastro-Intestinal Tract Carcinomas

“…Indeed, these results may emphasize the importance of MICA polymorphism in the development of CRC and GC or other cancer in our population. Similar associations of this variant with the malignant diseases, such as cutaneous malignant melanoma [26], hepatitis B virus-induced hepatocellular carcinoma [25], chronic and acute graft vs. host disease [22,26] and a number of autoimmune diseases, such as early-onset ankylosing spondylitis [21], rheumatoid arthritis [31], inflammatory bowel disease [32], systemic lupus erythematosus [33], Type 1 diabetes [34] and psoriatic disease [35]. Altogether, these data highlighted the potential role of MICA-129 in tumor and auto-immune susceptibility.…”

“…The functional consequence of MICA-129 variants is investigated in many studies. In patients with ulcerative colitis, the MICA-Val/Val was associated with higher sMICA serum levels [36] as well as in patients with hepatitis B virusinduced hepatocellular carcinoma and healthy controls [25]. But, it was unclear however whether the MICA-129 dimorphism has a direct effect on the generation of sMICA and affecting MICA shedding.…”

“…Alleles of MICA can be categorized into strong and weak binders of NKG2D based on the (rs1051792) A>G polymorphism at position 454 in the third exon of the MICA gene, which corresponds to amino acid 129 in the β 2- 129 polymorphism was associated with several pathologies [21][22][23][24][25][26][27][28]. However, MICA-129 polymorphism in gastric and colorectal cancer susceptibility has not been studied so far.…”

Association between hepatitis B virus and MHC class I polypeptide-related chain A in human hepatocytes derived from human-mouse chimeric mouse liver

“…Upregulation of NKG2D ligands on transformed cells suggests that cells have sensing mechanisms that recognize changes associated with transformation, thereby activating pathways that up-regulate the cell surface expression of NKG2D ligands [22]. It has been reported that MICA polymorphisms play a crucial role in modulating innate immune responses, tumor surveillance and regulating disease susceptibility during HBV infection [24].…”