TMEM17 Promotes The Malignant Progression Of Breast Cancer Via AKT/GSK3? Signaling

Objective:Breast cancer is the most common cancer in women worldwide.Thanks to huge advances in tumor diagnostic and therapeutic strategies,especially endocrine therapy,breast cancer mortality rates have steadily declined since the 1970 s.However,due to cancer cell metastasis and heterogeneity(especially Triple-negative breast cancer,TNBC),breast cancer is still one of the leading cause of cancer death in women.New biomarkers are need to be excavated for more accurate prognostic assessment and development of new targeted drugs.TMEM17(transmembrane protein 17)is one of the members of transmembrane protein(TMEM)family,which is involved in a number of physiological prosess,such as the formation of the plasma membrane of the ion channel,activation signal transduction pathway,mediated Cell chemotaxis,adhesion,apoptosis,autophagy and so on.Emerging more evidences show that TMEM protein family is closely linked to malignant progression and drug resistance of various cancers,meanwhile,the features and localization between the members of TMEM protein family are so different.Therefore,the functions of different members in different tumors deserve in-depth and detailed exploration.TMEM17 is a 198 amino acid protein encoded by a gene mapping to human chromosome 2,and was discovered as a cilium associated protein.Not long ago,another research group of our lab has reported TMEM17 was low expression in non-small cell lung cancer(NSCLC)and could depress invasion and metastasis of lung cancer cells.However,so far our knowledge on TMEM17 expression and biological functions in malignant tumors are still limited.In this study,we explored that TMEM17 expression in invasive breast cancer tissue and breast cell lines,and analyzed its relevances with clinicopathological factors.We also investigated the effects of TMEM17 on the biological behaviors of breast cancer cells,and further revealed the possible mechanism.Our studies provide a theoretical and experimental basis for the potential targeting of TMEM17 in the diagnosis and treatment of breast cancer.Methods:In this study,167 cases of invasive ductal carcinoma of the breast in the First Affiliated Hospital of China Medical University were selected for immunohistochemistry.Immunohistochemistry was used to detect the expression of TMEM17 in breast cancer tissues and normal tissues of 20 newly isolated specimens including breast cancer tissues and matched normal tissues and breast cancer cell lines.The breast cancer cells were transfected with si RNA for TMEM17,the effect of TMEM17 on breast cancer and its mechanism were studied by Western blotting,MTT,colony formation assay,wound healing assay and matrigel invasion assay.Results:TMEM17 expression was higher in cancerous tissues than in normal breast tissues(p = 0.015).Immunohistochemical staining of 167 invasive breast cancer specimens showed that TMEM17 expression was significantly increased in invasive breast cancer cells(10.78% vs 76.05%,p <0.001),compared with adjacent normal ductal glandular epithelial cells Correlated with T stage(p = 0.022),advanced TNM stage(p =0.007)and lymph node metastasis(p = 0.012).The results showed that TMEM17 overexpression could up-regulate the expression of p-AKT,p-GSK3?,active?-catenin and snail,and further increase the expression of downstream target proteins c-myc and cyclin D1,And reduce the expression of E-cadherin,promote the proliferation,invasion and migration of cancer cells,and the above experimental phenomenon can be reversed by the specific AKT inhibitor LY294002.Conclusion:Invasive breast cancer cells have TMEM17 cytoplasm overexpression,which is significantly associated with the malignant phenotype of breast cancer.TMEM17 promotes the proliferation,migration and invasion of breast cancer cells.TMEM17 can affect the biological behavior of breast cancer cells by up-regulating?-catenin,c-myc,cyclin D1,snail and down-regulating E-cadherin by AKT / GSK3?.