Kansas City VA Medical Center, Kansas City, Missouri, USA.
Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisina, USA.
J Cell Mol Med. 2022 Jan;26(2):399-409. doi: 10.1111/jcmm.17092. Epub 2021 Dec 3.
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-Kras ) 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.
酒精是胰腺癌的一个风险因素。然而，慢性酒精摄入影响胰腺癌发展的分子机制尚不清楚。我们最近的研究表明，慢性乙醇暴露于胰腺正常导管上皮细胞（HPNE）可通过产生癌症干细胞（CSC）诱导细胞转化。在这里，我们研究了慢性乙醇处理是否会诱导 HPNE 细胞发生上皮间质转化，并促进 KC（Pdx1-Cre 和 LSL-Kras）小鼠的胰腺癌发展。我们的数据表明，慢性乙醇暴露于 HPNE 细胞会诱导 SATB2 基因表达，使这些细胞变得高度迁移。乙醇处理 HPNE 细胞会导致 E-钙黏蛋白下调和 N-钙黏蛋白、Snail、Slug、Zeb1、Nanog 和 BMI-1 上调。在乙醇转化的 HPNE 细胞中抑制 SATB2 表达会抑制 EMT 表型。用含乙醇饮食喂养的 KC 小鼠比用对照饮食喂养的小鼠表现出更强的胰腺癌细胞生长和发展。用含乙醇饮食喂养的 KC 小鼠的胰腺显示出更高的干细胞标志物（CD133、CD44、CD24）、多能性维持因子（cMyc、KLF4、SOX-2 和 Oct-4）、N-钙黏蛋白、EMT 转录因子（Snail、Slug 和 Zeb1）的表达，以及更低的 E-钙黏蛋白表达，比用对照饮食喂养的小鼠的胰腺。此外，用含乙醇饮食喂养的 KC 小鼠的胰腺显示出更高的炎症细胞因子（TNF-α、IL-6 和 IL-8）和 PTGS-2（COX-2）基因的表达，比用对照饮食喂养的小鼠的胰腺。这些数据表明，慢性酒精摄入可能通过产生炎症信号和 CSC 促进胰腺癌的发展。
