Dysregulation of miR-31 and miR-21 Induced by Zinc Deficiency Promotes Esophageal Cancer

Presented at: Hallmarks and Cancer Conference, October 29-31 in San Francisco. And AICR Annual Meeting, November 1-2, 2012. Dietary zinc (Zn) deficiency (ZD) in rats induces an inflammatory gene signature that fuels esophageal squamous cell cancer (ESCC). Using nanoStringTM technology, we show that the inflammation is accompanied by altered expression of specific microRNAs in esophagus, as well as skin, lung, pancreas, liver, prostate, and PBMC, predictive of disease development. Particularly, the ZD esophagus has a microRNA signature resembling human ESCC/tongue SCC miRNAomes with overexpression of miR-31 and miR-21 and downregulation of their respective tumor suppressor targets PPP2R2A and PDCD4. Esophageal miR-31 and miR-21 levels are directly associated with the appearance of ESCC. In situ hybridization localizes miR-31 to tumor and miR-21 to stromal cells, establishing their cell-type specificity. In regressing tongue SCCs from Zn-supplemented rats, miR-31 and miR-21 expression was concomitantly reduced, establishing their responsiveness to Zn-therapy. A search for putative microRNA targets revealed a bias toward genes in inflammatory pathways. Thus, ZD induces inflammation-associated microRNAs and promotes ESCC1