Collagen I promotes hepatocellular carcinoma cell proliferation by regulating integrin β1/FAK signaling pathway in nonalcoholic fatty liver

Nonalcoholic fatty liver disease (NAFLD) has become a major risk factor for hepatocellular carcinoma (HCC) worldwide. However, the underlying mechanism remains insufficiently elucidated. The expression of Collagen I, an important component of extracellular matrix (ECM), was increased during the progression from simple steatosis to NASH. The purpose of this study was to investigate the role of Collagen I in NAFLD-related HCC. To study this, the decellularized liver matrix, which preserves the pathological changes of ECM, was prepared from the human fatty liver (FLM) and human normal liver (NLM). HepG2 cells cultured in FLM had a higher proliferation rate than those in NLM. SMMC-7721 and HepG2 cells cultured on Collagen I-coated plates grew faster than those on either Collagen IV- or fibronectin-coated plates. This effect was dose-dependent and associated with elevated integrin beta 1 expression and activation of downstream phospho-FAK. Knocking down the expression of integrin beta 1 significantly decreased the proliferation of HCC cells. Additionally, an orthotopic tumor model was established in NAFLD mice at different stages. The over-expressed Collagen I in the mice liver increased the expression of integrin beta 1 and downstream phospho-FAK, resulting in the proliferation of HCC cells. This proliferation could be inhibited by blocking the integrin beta 1/FAK pathway. In summary, our study demonstrated that Collagen I promoted HCC cell proliferation by regulating the integrin beta 1/FAK pathway. Decellularized liver matrix can be used as a platform to three-dimensionally culture HCC cells and reproduce the impact of changed ECM on the progression of NAFLD-related HCC.