CK2α phosphorylates DBC1 and is involved in the progression of gastric carcinoma and predicts poor survival of gastric carcinoma patients

Abstract

CK2 has diverse effects on the tumorigenesis owing to its kinase activity, which phosphorylates various proteins involved in tumorigenesis. We, therefore, investigated the expression and role of CK2 in the phosphorylation of deleted in breast cancer 1 (DBC1) in gastric carcinomas. We used 187 gastric carcinomas and human gastric cancer cells to investigate the roles and relationship between CK2 and DBC1 in gastric carcinomas. Positive expression of CK2 and phospho-DBC1 predicted shorter overall survival and relapse-free survival by univariate analysis. Especially, CK2 expression was an independent prognostic indicator for gastric carcinoma patients. In gastric carcinoma cells, CK2 was bound to DBC1 and phosphorylated DBC1. The phosphorylation of DBC1 by CK2 was evidenced by co-immunoprecipitation of CK2 and DBC1 in a GST pull-down assay, an in vitro kinase assay, and immunofluorescence staining. Inhibition of both CK2 and DBC1 decreased proliferation and invasive activity of cancer cells. Decreased migration and invasive activity was associated with a downregulation of MMP2, MMP9 and the epithelial-mesenchymal transition. A mutation at the phosphorylation site of DBC1 also downregulated the signals related with the epithelial-mesenchymal transition. Our study demonstrated that CK2 is an independent prognostic indicator for gastric carcinoma patients and is involved in tumorigenesis by regulating the phosphorylation of DBC1. In addition, the blocking of CK2 and DBC1 inhibited the proliferation and invasive potential of gastric cancer cells. Therefore, our study suggests that CK2-DBC1 pathway might be a new therapeutic target for the treatment of gastric carcinoma. What's new? A number of proteins that are involved in tumorigenesis are influenced by the protein kinase CK2, and the expression of CK2 specifically is known to be modified in certain cancers, suggesting possible effects on tumor development and progression. The present study indicates that CK2 is an independent prognostic indicator of gastric carcinoma and is involved in tumorigenesis by regulating the phosphorylation of the potentially oncogenic protein DBC1 (deleted in breast cancer 1). Inhibition of CK2 or DBC1 attenuated proliferation and invasion activity of cancer cells, suggesting that the CK2-DBC1 pathway may be a therapeutic target for gastric carcinoma.