Zinc deficiency (ZD) increases the risk of esophageal squamous cell carcinoma 
(ESCC). In a rat model, chronic ZD induces an inflammatory gene signature that 
fuels ESCC development. microRNAs regulate gene expression and are aberrantly 
expressed in cancers. Here we investigated whether chronic ZD (23 weeks) also 
induces a protumorigenic microRNA signature. Using the nanoString technology, we 
evaluated microRNA profiles in ZD esophagus and six additional tissues (skin, 
lung, pancreas, liver, prostate and peripheral blood mononuclear cells [PBMC]). 
ZD caused overexpression of inflammation genes and altered microRNA expression 
across all tissues analyzed, predictive of disease development. Importantly, the 
inflammatory ZD esophagus had a distinct microRNA signature resembling human 
ESCC or tongue SCC miRNAomes with miR-31 and miR-21 as the top-up-regulated 
species. Circulating miR-31 was also the top-up-regulated species in PBMCs. In 
ZD esophagus and tongue, oncogenic miR-31 and miR-21 overexpression was 
accompanied by down-regulation of their respective tumor-suppressor targets 
PPP2R2A and PDCD4. Importantly, esophageal miR-31 and miR-21 levels were 
directly associated with the appearance of ESCC in ZD rats, as compared with 
their cancer-free Zn-sufficient or Zn-replenished counterparts. In situ 
hybridization analysis in rat and human tongue SCCs localized miR-31 to tumor 
cells and miR-21 to stromal cells. 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. Our finding that 
ZD causes miR-31 and miR-21 dysregulation associated with inflammation provides 
insight into mechanisms whereby ZD promotes ESCC.