Ethanol exposure of human pancreatic normal ductal epithelial cells induces EMT phenotype and enhances pancreatic cancer development in KC (Pdx1‐Cre and LSL‐KrasG12D) mice

Abstract

Alcohol is a risk factor for pancreatic cancer. However, the molecular mechanism by which chronic alcohol consumption influences pancreatic cancer development is not well understood. We have recently demonstrated that chronic ethanol exposure of pancreatic normal ductal epithelial cells (HPNE) induces cellular transformation by generating cancer stem cells (CSCs). Here, we examined whether chronic ethanol treatment induces epithelial–mesenchymal transition in HPNE cells and promotes pancreatic cancer development in KC (Pdx1‐Cre, and LSL‐KrasG12D) mice. Our data demonstrate that chronic ethanol exposure of HPNE cells induces SATB2 gene and those cells became highly motile. Ethanol treatment of HPNE cells results in downregulation of E‐Cadherin and upregulation of N‐Cadherin, Snail, Slug, Zeb1, Nanog and BMI‐1. Suppression of SATB2 expression in ethanol‐transformed HPNE cells inhibits EMT phenotypes. KC mice fed with an ethanol‐containing diet show enhanced pancreatic cancer growth and development than those fed with a control diet. Pancreas isolated from KC mice fed with an ethanol‐containing diet show higher expression of stem cell markers (CD133, CD44, CD24), pluripotency‐maintaining factors (cMyc, KLF4, SOX‐2, and Oct‐4), N‐Cadherin, EMT‐transcription factors (Snail, Slug, and Zeb1), and lower expression of E‐cadherin than those isolated from mice fed with a control diet. Furthermore, pancreas isolated from KC mice fed with an ethanol‐containing diet show higher expression of inflammatory cytokines (TNF‐α, IL‐6, and IL‐8) and PTGS‐2 (COX‐2) gene than those isolated from mice fed with a control diet. These data suggest that chronic alcohol consumption may contribute to pancreatic cancer development by generating inflammatory signals and CSCs.