Oncogenic potential of Cyclin Kinase Subunit-2 in cholangiocarcinoma

摘要

Background: Cyclin kinase subunit-2 (Cks2), a member of the human Cks family, plays an important role in the regulation of meiosis and mitosis; and its abnormal expression is usually associated with carcinogenesis. However, its exact functions and molecular mechanisms remain unclear. Aims: To observe Cks2 expression in cholangiocarcinoma and explore its role in the carcinogenesis of cholangiocarcinoma and possible mechanism. Methods: Cks2 expression in cholangiocarcinoma was detected with immunostaining and RT-PCR. MTT, colony formation, immunofluorescence, flow cytometry and Western blotting were performed to explore the role of Cks2 in cholangiocarcinoma and possible mechanism. Results: Cks2 was significantly elevated in cholangiocarcinoma tissues and its over-expression was associated with poor differentiation, CA19-9 and poor prognosis. Furthermore, Cks2 down-regulation inhibited cholangiocarcinoma cell proliferation and colony formation in vitro, and the growth of cholangiocarcinoma xenografts in animals; especially, enhanced the sensitivity of cholangiocarcinoma cells to chemotherapy. We further found that Cks2 knockdown induced cholangiocarcinoma cell cycle arrest in G2/M phase through down-regulation of Cyclin A and Cyclin B1 and Bax up-regulation and activation, mitochondrial membrane permeabilization and caspase-3 activation, which resulted in facilitating cholangiocarcinoma apoptosis. Conclusions: These findings suggest that Cks2 may serve as an independent prognostic factor in patients with cholangiocarcinoma, and play an important role in the carcinogenesis of cholangiocarcinoma by facilitating cell cycle progression and Bax-mediated mitochondrial caspase-dependent apoptosis.