Abstract
BackgroundSorafenib is the first-line treatment for advanced-stage hepatocellular carcinoma (HCC). Several studies have shown that the up-regulation of β-catenin plays a role in sorafenib resistance in HCC; however, the mechanism associated with this phenomenon remains elusive.MethodsWestern blotting, flow cytometry, and an evaluation of IC50 values were used to confirm the role of β-catenin in HCC sorafenib resistance. Immunoprecipitation and western blotting were then performed to identify regulatory interactions between β-catenin and Nek2. Further, western blotting, flow cytometry, and an in vivo xenograft model were used to evaluate the function of Nek2 in HCC sorafenib resistance, whereas rescue experiments were performed to confirm that Nek2 induces sorafenib resistance via β-catenin. Finally, western blotting and immunohistochemistry were used to evaluate the expression level of Nek2 in paired HCC and non-tumor tissues.ResultsWe showed that β-catenin could suppress sorafenib-induced apoptosis and cell growth inhibition in HCC cell lines. By screening β-catenin-interacting proteins, we found that Nek2 could bind β-catenin in sorafenib-treated HCC cell lines. Our results also showed that Nek2 stabilizes β-catenin and promotes its translocation to the nucleus, consequently activating the transcription of downstream target genes. We further confirmed that Nek2 could induce sorafenib resistance in HCC cell lines, and that β-catenin was the key element involved in this process. Further, a xenograft tumor model showed that Nek2 knockdown could improve the anti-tumor effect of sorafenib, whereas an analysis of tumor proteins showed that Nek2 regulates β-catenin protein levels and its nuclear translocation in vivo. In addition, Nek2 was found to be up-regulated in HCC tissue, and especially in advanced-stage disease.ConclusionsOur study proves that Nek2 induces HCC sorafenib resistance via β-catenin and suggests a novel therapeutic strategy to improve the anti-tumor effects of sorafenib in HCC.
Highlights
Sorafenib is the first-line treatment for advanced-stage hepatocellular carcinoma (HCC)
Our study proves that NIMA-related kinase 2 (Nek2) induces HCC sorafenib resistance via β-catenin and suggests a novel therapeutic strategy to improve the anti-tumor effects of sorafenib in HCC
Results β-Catenin/Wnt signaling induces sorafenib resistance in hepatocellular carcinoma Consist with previous studies, our experiment showed that after 24 h of sorafenib treatment, levels of β-catenin and its downstream target genes including cMyc and CyclinD1 were upregulated in SMMC-7721, MHCC-97H, and SK-Hep1 HCC cell lines (Additional file 1: Figure S1a)
Summary
Sorafenib is the first-line treatment for advanced-stage hepatocellular carcinoma (HCC). Several studies have shown that the up-regulation of β-catenin plays a role in sorafenib resistance in HCC; the mechanism associated with this phenomenon remains elusive. Hepatocellular cancer (HCC) comprises 90% of liver cancer cases [2, 3]. Despite efforts to elucidate the mechanisms associated with HCC and the burden it caused [5, 6], the understanding of this disease is still limited and treatment options are not optimal. A multi-target tyrosine kinase inhibitor, was the only systemic therapy for advanced-stage HCC patients from 2007 to 2016 and it remains the first-line treatment for these patients [7]. A systematic understanding of the mechanisms associated with sorafenib resistance is critical to improve treatment options for HCC patients
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