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

Abstract

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 β1 expression and activation of downstream phospho-FAK. Knocking down the expression of integrin β1 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 β1 and downstream phospho-FAK, resulting in the proliferation of HCC cells. This proliferation could be inhibited by blocking the integrin β1/FAK pathway. In summary, our study demonstrated that Collagen I promoted HCC cell proliferation by regulating the integrin β1/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.

COL4A1 promotes the growth and metastasis of hepatocellular carcinoma cells by activating FAK-Src signaling

“…As shown in Additional le6: Figure S3, knockdown of COL4A2 in SMM7721 and SK-Hep1 by siRNA could inhibit the proliferation and migration of those cells. In addition, COL1A1 has been shown to promote HCC progression [17,40,41]. We also found that knockdown of COL1A1 inhibited the proliferation and migration of SMM7721 and SK-Hep1 cells (Additional le7: Figure S4).…”

“…However, only a few studies on the expression and function of collagen genes have been reported in HCC. Some studies reported that COL1A1 was upregulated in HCC and could promote HCC progression [17,40,41]. Based on bioinformatics analysis, Liu et al reported that COL4A1 and COL4A2 were signi cantly correlated with hepatocarcinogenesis and HCC progression [56].…”

Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

“…Type I collagen Activates HSCs and promotes fibrosis through integrin β1/YAP signaling 52 Activates TGF-β through integrin αv signal 53 Induces invasion and proliferation of HSCs through DDR2 55,56 Blocking integrin αv by a small molecule attenuated fibrosis 54 Promotes HCC proliferation through integrin ß1/FAK signaling in NASH 162 Promotes EMT of tumor cells through DDR2 129,163 Type IV collagen Increases in fibrotic livers and consists basement membrane 164,165 VEGF promotes angiogenesis by regulating type IV collagen receptor, integrin α2β1 166 Arrestin (fragments from type IV collagen) suppresses endothelial cell proliferation, migration, and angiogenesis through integrin αv/ β3 167…”

Contributions of Fibroblasts, Extracellular Matrix, Stiffness, and Mechanosensing to Hepatocarcinogenesis

“…For example, integrin β1, β4, α6, and α2 are upregulated in HCC patients as well as in HCC cell lines, and positively correlate with the pathologic grade and outcomes. [86][87][88][89][90] Single-nucleotide polymorphisms in integrin αV influence HCC growth in patients. 91 In contrast, integrin β3 is downregulated in human HCC, 92 and integrin α9 is negatively correlated with HCC growth and metastasis.…”