Molecular mechanism of ANO TMEM16-mediated cell growth in pancreatic cancer

Abstract

Pancreatic cancer has a very poor prognosis and search for druggable target is unmet medical needs. TMEM16 family genes consist of 10 genes that range from TMEM16A to TMEM16K. Of these genes, TMEM16A, TMEM16B, and TMEM16F are known as ion channels. In addition TMEM16C, TMEM16D, TMEM16F, TMEM16G, and TMEM16J are reported as phospholipid scramblase, but their exact physiological function is not yet known. TMEM16A is most well known gene in TMEM16 family and is over-expressed in various cancer types. However, the role of TMEM16A in gastrointestinal cancer, such as pancreatic cancer, has not been revealed. Here we show that TMEM16A promotes cell proliferation in pancreatic cancer cell lines and low chloride status induced by TMEM16A is important mechanism for cell proliferation. In addition, we find that TMEM16J is over-expressed in pancreatic cancer and it has a role of promoting cell proliferation via EGFR over-expression and MAPK pathway activation. Furthermore, pancreatic cancer patients with low expression of TMEM16A and TMEM16J show prolonged survival outcomes than patients with high expression of TMEM16A and TMEM16J. These results indicate that TMEM16A and TMEM16J can be new druggable targets for anti-cancer therapy and have a role as a prognostic factor for survival outcomes in pancreatic cancer. It enables accurate patient risk stratification and may aid in treatment selection.