Abstract
BACKGROUND: Although the prognosis of hepatocellular carcinoma (HCC) has been improved significantly due to diagnostic innovation and treatment optimization, HCC remains highly lethal, necessitating novel therapeutic targets. MATERIALS AND METHODS: CDK8 expression was assessed in 75 HCC and paracancerous tissues by immunohistochemistry. Integrated analysis of 3969 HCC and 3245 non-tumor liver samples from RNA-seq and microarray datasets was performed. CDK8's functional mechanisms were explored through genetic alteration, immune infiltration, co-expression networks, and single-cell RNA-seq analyses. In vitro experiments including cell proliferation assay, scratch assay and transwell assay were conducted for investigating the effect of combined use of CDK8 inhibitor MSC2530818 and sorafenib on the biological functions of Huh7 cells. RESULTS: CDK8 was significantly overexpressed in HCC tissues, correlating with immune cell infiltration and advanced clinical stage. Single-cell analysis revealed prominent CDK8 expression in T/NK cells, myeloid cells, and cancer cells from advanced HCC samples. The carcinogenic role of CDK8 in HCC might be explained by the enrichment of co-expressed genes in biological processes including mRNA metabolic process, cell division and DNA conformation change. Combination of CDK8 inhibitor and sorafenib exerted more potent inhibition on cell growth, migration and invasion of Huh7 cells than monotherapy. CONCLUSION: CDK8 is highly expressed in HCC tissues, suggesting its oncogenic role. Our in vitro findings demonstrate that the CDK8 inhibitor MSC2530818 synergizes with sorafenib to enhance anti-tumor efficacy against HCC cells, supporting further investigation of this combination strategy.