In addition to the influence of the inflammatory environment, immune cells in the microenvironment are critically associated with the carcinogenic processes. Nonalcoholic injury-mediated liver inflammation results in the production of diverse cytokines, which can facilitate ECM production for preneoplastic progression and eventual carcinogenesis.
Specifically, the excessive ECM deposition during fibrosis and cirrhosis activates abnormal cell proliferation signaling for HCC development.
Altogether, these findings suggest that TM4SF5-mediated STAT3 activity for extracellular matrix modulation is involved in the progression of liver disease to HCC and that TM4SF5 appears to suppress NK cells during liver carcinogenesis.Ĭhronic liver injury progressively causes liver diseases, including nonalcoholic fatty liver disease (NAFLD), via excessive production of the extracellular matrix (ECM), which drives fibrosis and cirrhosis and ultimately results in hepatocellular carcinoma (HCC). TM4SF5 suppression or inhibition reduced STAT3 signaling activity and recovered the receptor levels and NK cell surveillance, leading to reduced fibrotic and cancerous phenotypes, and longer survival. TM4SF5 expression in cancer cells downregulated stimulatory ligands and receptors for NK cell cytotoxicity, including SLAMF6, SLAMF7, MICA/B, and others. TM4SF5-dependent tumorigenesis involved natural killer (NK) cell exhaustion-like phenotypes including the reduction of NK cell number or function, which were blocked with TSAHC treatment. These TM4SF5-mediated effects were abolished by TM4SF5 inhibitor, 4′-( p-toluenesulfonylamido)-4-hydroxychalcone (TSAHC). TM4SF5-transgenic and diethylnitrosamine (DEN)-induced liver cancer mouse models exhibited fibrotic and cancerous livers, respectively, with enhanced TM4SF5, pY 705STAT3, collagen I, and laminin γ2 levels. We investigated how TM4SF5-mediated signaling caused immune evasion using in vitro primary cells and in vivo liver tissues from genetic or chemically induced mouse models. Although transmembrane 4 L six family member 5 (TM4SF5) is involved in liver fibrosis and cancer, its mechanism avoiding immune surveillance during carcinogenesis remains unknown. Aberrant extracellular matrix and immune cell alterations within the tumor microenvironment promote the pathological progression of liver carcinogenesis.
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