Background: Since its introduction in 2008, sorafenib has remained the standard first-line systemic treatment for advanced hepatocellular carcinoma (HCC). Nevertheless, its clinical benefits are often compromised by the rapid emergence of drug resistance. This study explores the molecular mechanisms underlying sorafenib resistance, with particular emphasis on the involvement of connective tissue growth factor (CCN2/CTGF) in the regulation of c-Met signaling pathways. Methods: We began by evaluating CCN2 expression levels in HCC tissue samples via immunohistochemistry and analyzing their correlation with clinicopathological characteristics. To functionally characterize CCN2, we established stable HCC cell lines with either knockdown or overexpression of the gene using lentiviral transduction. The effects of CCN2 on cellular proliferation and drug resistance were evaluated using cell counting kit-8 (CCK-8) and colony formation assays. To elucidate the downstream signaling mechanisms, a tyrosine kinase PCR array was employed to identify expression changes within the tyrosine kinase superfamily after CCN2 knockdown. Further investigation into the molecular mechanism by which CCN2 promotes sorafenib resistance was conducted using real-time quantitative PCR (RT-qPCR), western blotting, and immunofluorescence. Finally, the therapeutic potential of co-targeting CCN2 and sorafenib was validated in a nude mouse xenograft tumor model. Results: Our results establish that CCN2 overexpression significantly enhances HCC proliferation, while also inducing resistance to sorafenib. Mechanistically, we identified that CCN2 binds to integrin αV, triggering focal adhesion kinase (FAK) phosphorylation, which in turn promotes yes-associated protein (YAP) nuclear translocation and leads to the transcriptional upregulation of c-Met. This proposed signaling axis was consistently supported by tyrosine kinase PCR array, co-immunoprecipitation, and western blot analyses. Ultimately, in vivo experiments confirmed that simultaneously targeting CCN2 and administering sorafenib produces a synergistic effect, markedly inhibiting tumor growth and restoring therapeutic sensitivity. Conclusion: These results not only elucidate a novel CCN2/FAK/YAP/c-Met axis in sorafenib resistance but also provide a mechanistic rationale for dual-targeting strategies to improve outcomes in advanced HCC.
Cui et al. (Fri,) studied this question.
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