Downregulation of SSR2 Enhances Hepatocellular Carcinoma Cisplatin Sensitivity via the Hippo Pathway

Background: Chemotherapy resistance is an obstacle to promoting the survival of patients with hepatocellular carcinoma (HCC). Thus, finding promising therapeutic targets to enhance HCC chemotherapy is necessary. Methods: Signal sequence receptor subunit (SSR2) expression analysis was performed using quantitative real time polymerase chain reaction (qPCR) and Western blotting assays. Colony formation, apoptosis, anchorage-independent growth assay, and in vivo animal models were used to investigate the effect of SSR2 expression on the resistance of HCC cells to Cisplatin (DDP). Western blotting and luciferase reporter gene techniques were used to explore the molecular mechanism of SSR2 on the resistance of HCC cells to DDP. Results: We found that the SSR2 is upregulated in HCC and associated with poor survival. Further analysis showed that the downregulation of SSR2 increased the sensitivity of HCC to DDP. Mechanically, SSR2 inhibited the Yes-associated protein (YAP) phosphorylation and promoted the transcription of Hippo signaling downstream genes. Finally, the Hippo pathway inhibitor can suppress colony formation and tumorigenesis arising from SSR2 upregulation. Conclusions: Our study shows that SSR2 is important in HCC progression via the Hippo pathway. Thus, targeting the SSR2/Hippo axis might be a potential strategy for overcoming HCC resistance to DDP.