Cross-talk between the TM4SF5/FAK and the IL6/STAT3 pathways renders immune escape of human liver cancer cells

Abstract

TM4SF5 overexpressed in hepatocellular carcinoma activates FAK during tumor cell migration. However, it remains unknown how TM4SF5 in hepatocellular carcinoma cells compromise with immune actions initiated by extracellular cytokines. Normal and cancerous hepatocytes with or without TM4SF5 expression were analyzed for the effects of cytokine signaling activity on TM4SF5/FAK signaling and metastatic potential. We found that IL6 was differentially expressed in hepatocytes depending on cancerous malignancy and TM4SF5 expression. IL6 treatment activated FAK and STAT3 and enhanced focal adhesion (FA) formation in TM4SF5-null cells, but it decreased TM4SF6-dependent FAK activity and FAformation in SNU761-TM4SF5 cells. STAT3 suppression abolished the IL6-mediated effects in normal Chang cells, but it did not recover the TM4SF5-dependent FAK activity that was inhibited by IL6 treatment in cancerous SNU761-TM4SF5 cells. In addition, modulation of FAK activity did not change the IL6-mediated STAT3 activity in either the Chang or SNU761 cell system. TM4SF5 expression in SNU761 cells caused invasive extracellular matrix degradation negatively depending on IL6/IL6R signaling. Thus, it is likely that hepatic cancer cells might adopt TM4SF5-dependent FAK activation and metastatic potential by lowering IL6 expression and thus avoiding its immunological action through the IL6-STAT3pathway.