机构：[1]Department of Tumor Immunotherapy, Fourth Hospital of Hebei MedicalUniversity and Hebei Cancer Institute, Tianshan Street 169, Shijiazhuang,China河北医科大学第四医院肿瘤免疫科.东临床科室[2]Department of Toxicology, Hebei Medical University, Shijiazhuang,China[3]State Key Laboratory of Molecular Biology, Institute of Basic MedicalSciences, Chinese Academy of Medical Sciences & Peking Union Medical College,Beijing, China
Background Bridging integrator 1 (BIN1) has showed outstanding tumor-suppressive potential via inhibiting c-MYC-mediated tumorigenesis. However, a frequent phosphorylation of c-MYC at Ser-62 site could block the BIN1/c-MYC interaction and limits the tumor-suppressive effect of BIN1. Cyclin-dependent kinase 5 (CDK5), a generally dysregulated protein in various carcinomas, can mediate c-MYC phosphorylation at Ser-62 site. However, whether the existence of CDK5 could block the BIN1/c-MYC interaction remains unclear. Materials and methods The expression of CDK5 and BIN1 in non-small cell lung cancer (NSCLC) cell lines were measured. CDK5 was knocked down and overexpressed in H460 and PC9 cells, respectively. CCK-8, wound healing and transwell were used to detect the proliferation, migration and invasion ability of NSCLC cells. Tumor-bearing nude mouse model was built with H460 cells. Dinaciclib was added to realize the effect of CDK5 inhibition in vivo. NSCLC and matched para-carcinoma specimens were collected from 153 patients who underwent radical operation. IHC was performed to determine the expression of CDK5 in the specimens. Kaplan-Meier analysis was used to analyze the correlation between the postoperative survival and CDK5 expression. Results CDK5 was highly expressed in H460 cells, and knockdown of CDK5 could restore the BIN1/c-MYC interaction. Meanwhile, low expression of CDK5 was observed in PC9 cells, and overexpression of CDK5 blocked the BIN1/c-MYC interaction. Consequently, the growth, migration, invasion and epithelial mesenchymal transition (EMT) ability of H460 and PC9 cells could be facilitated by CDK5. The addition of CDK5 inhibitor Dinaciclib significantly suppressed the tumorigenesis ability of NSCLC cells in tumor-bearing mouse model. Furthermore, high expression of CDK5, along with low expression of BIN1, could predict poor postoperative prognosis of NSCLC patients. The patients with high expression of CDK5 and low expression of BIN1 showed similar prognosis, indicating that CDK5 could neutralize the tumor suppressing effect of BIN1 in clinical situation. Conclusions CDK5 blocked the interaction of BIN1 and c-MYC via promoting phosphorylation of c-MYC at ser-62 site, ultimately facilitated the progression of NSCLC.
基金：
National Natural Science Foundation of China, Grant Numbers: 81201607,
81871894.
第一作者机构：[1]Department of Tumor Immunotherapy, Fourth Hospital of Hebei MedicalUniversity and Hebei Cancer Institute, Tianshan Street 169, Shijiazhuang,China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Tumor Immunotherapy, Fourth Hospital of Hebei MedicalUniversity and Hebei Cancer Institute, Tianshan Street 169, Shijiazhuang,China
推荐引用方式(GB/T 7714)：
Xiangyu Zhang,Jiali Wang,Yunlong Jia,et al.CDK5 neutralizes the tumor suppressing effect of BIN1 via mediating phosphorylation of c-MYC at Ser-62 site in NSCLC[J].CANCER CELL INTERNATIONAL.2019,19(1):doi:10.1186/s12935-019-0952-5.
APA：
Xiangyu Zhang,Jiali Wang,Yunlong Jia,Tianxu Liu,Mengjie Wang...&Lihua Liu.(2019).CDK5 neutralizes the tumor suppressing effect of BIN1 via mediating phosphorylation of c-MYC at Ser-62 site in NSCLC.CANCER CELL INTERNATIONAL,19,(1)
MLA：
Xiangyu Zhang,et al."CDK5 neutralizes the tumor suppressing effect of BIN1 via mediating phosphorylation of c-MYC at Ser-62 site in NSCLC".CANCER CELL INTERNATIONAL 19..1(2019)
