Abstract
Dysregulated potassium (K+) channels have previously been shown to promote the development and progression of many types of cancers. Meanwhile, K+ channels are particularly important in regulating the endocrine and exocrine functions of pancreas. However, the expression pattern and prognostic significance of K+ channels in pancreatic ductal adenocarcinoma (PDAC) remain unknown. In this study, by screening a GEO dataset containing 36 microdissected PDAC and matching normal pancreatic tissue samples, four differentially expressed K+ channels (KCNJ5, KCNJ16, KCNN4 and KCNK1) were identified in PDAC. by immunohistochemical analysis of pancreatic tissue sections from Pdx1-Cre; LSL-KrasG12D/+ mice (KC), Pdx1-Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ mice (KPC) and human PDAC tissue microarrays, we found that Ca2+-activated K+ channel KCNN4 was significantly elevated in pancreatic intraepithelial neoplasia (PanIN) and PDAC epithelia compared with untransformed pancreas tissues. Higher epithelial KCNN4 expression was closely correlated with advanced TNM stages and predicted a poor prognosis in patients with PDAC. Elevated KCNN4 expression was significantly associated with shorter survival in univariable and multivariable analyses. Collectively, the identification of expression pattern of K+ channels in PDAC and its precursor PanIN demonstrates the importance of KCNN4 channel during the malignant transformation of PDAC. On the basis of the prognostic signals from two independent cohorts, KCNN4 should be considered as a promising therapeutic target.