Original ArticleCDK5RAP3 acts as a tumor suppressor in gastric cancer through inhibition of β-catenin signaling

•Down-regulation of CDK5RAP3 in gastric cancer was correlated with poor prognosis.•CDK5RAP3 suppressed gastric cancer tumorigenesis via β-catenin inhibition.•CDK5RAP3 inhibited β-catenin via GSK-3β phosphorylation suppression.•The prognostic value of CDK5RAP3 in gastric cancer depends on β-catenin status.

CDK5RAP3 was isolated as a binding protein of the Cdk5 activator p35. Although CDK5RAP3 has been implicated in cancer progression, its expression and function have not been investigated in gastric cancer. Our study demonstrated that the mRNA and protein levels of CDK5RAP3 were markedly decreased in gastric tumor tissues when compared with respective adjacent non-tumor tissues. CDK5RAP3 in gastric cancer cells significantly reduced cell proliferation, migration, invasion and tumor xenograft growth through inhibition of β-catenin. Secondly, CDK5RAP3 was found to suppress the phosphorylation of GSK-3β (Ser9), leading to the phosphorylation (Ser37/Thr41) and subsequent degradation of β-catenin. Lastly, the prognostic value of CDK5RAP3 for overall survival was found to be dependent on β-catenin cytoplasm/nucleus localization in human gastric cancer samples. Collectively, our results demonstrated that CDK5RAP3 negatively regulates the β-catenin signaling pathway by repressing GSK-3β phosphorylation and could be a potential therapeutic target for gastric cancer.