Abstract
BackgroundCDK5, an atypical member of the CDK family, play a significant role in the tumorigenesis of multiple organ, but CDK5 and its substrates in genesis and development of HCC is still unclear.MethodsExpression of CDK5 in HCC tumor and paired adjacent noncancerous tissues from 90 patients were measured by Western blotting, immunohistochemistry, and real-time PCR. The role of CDK5 in cell function and tumorigenesis was explored in HCC cell lines, ex vivo xenografts and diethylnitrosamine induced HCC model. Furthermore, comparative phosphoproteomic screening identified the oncoprotein TPX2 as a new substrate of CDK5. We also identified the effect of CDK5/P25 interaction blocker tamoxifen on HCC cell growth and migration.ResultsCDK5 was increased in HCC tisues and the level of CDK5 was correlated with the severity of HCC based on patient recurrence and 5-year fatality rate. Exogenously expressed CDK5 but not kinase-dead CDK5 promoted proliferation, migration, and invasion of HCC cells. Functional ablation of CDK5 significantly inhibited the exacerbation of HCC cells. Xenograft implantation of HCC cells overexpressing CDK5 promoted tumorigenesis, and genetic knockdown of CDK5 reduced HCC growth and metastasis in vivo. More importantly, heterozygous knockout CDK5 (Cdk5+/−) attenuated HCC tumorigenesis induced by diethylnitrosamine. CDK5-mediated phosphorylation of TPX2 at serine 486 promoted its protein stability. TPX2 silence could restore HCC cell migration capability with overexpression CDK5. Treatment with tamoxifen inhibited cell growth and migration of HCC, demonstrating the role of active CDK5 in HCC.ConclusionsOur results suggest activation of CDK5 is associated with HCC tumorigenesis. CDK5-mediated phosphorylation and stabilization of TPX2 promotes hepatocellular proliferation and tumorigenicity.
Highlights
Cyclin-dependent kinase 5 (CDK5), an atypical member of the cyclin-dependent kinases (CDKs) family, play a significant role in the tumorigenesis of multiple organ, but CDK5 and its substrates in genesis and development of Hepatocellular carcinoma (HCC) is still unclear
Enhanced CDK5 levels in HCC tissues are associated with poor prognosis in HCC cancer We examined CDK5 protein levels in HCC tumors and paired adjacent noncancerous tissues from 66 patients by western blotting
We observed that HCC tumor tissues expressed significantly higher levels of CDK5 compared with noncancerous tissues in the majority of patients (63.3%, Fig. 1a)
Summary
CDK5, an atypical member of the CDK family, play a significant role in the tumorigenesis of multiple organ, but CDK5 and its substrates in genesis and development of HCC is still unclear. Abnormal expression and activation of cyclin-dependent kinases (CDKs) contribute to tumorigenesis of certain types of cancers [4, 5]. Accumulating evidence suggests that CDK5 may play a significant role in the tumorigenesis. Elevated CDK5 and its kinase activity have been reported in different types of cancers including breast cancer, lung cancer, liver cancer, pancreatic cancer, thyroid carcinoma, and myeloma [9, 13,14,15,16]. CDK5 plays a significant role in tumor progression and metastasis. The downstream substrates of CDK5 during HCC progression, which are important to demonstrate the function of CDK5 and develop therapeutic drugs for HCC, are still unknown
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