Abstract LB-241: Silencing of microRNA-31 prevents esophageal neoplasia in zinc deficient rats.

Taccioli, Cristian; Chen, Hongping; Garofalo, Michela; Jiang, Yubao; Di Leva, Gianpiero; Alder, Hansjuerg; Middleton, Justin; Smalley, Karl J.; Bottoni, Arianna; Costinean, Stefan; Farber, John L.; Croce, Carlo M.; Fong, Louise Y Y

Abstract

Dietary zinc deficiency (ZD) is implicated in the pathogenesis of human esophageal squamous cell carcinoma (ESCC). microRNA-31 (miR-31) is overexpressed in human ESCC. In the rat a ZD diet promotes esophageal carcinogenesis by inducing cellular proliferation and changes in the expression of microRNA and mRNA, including overexpression of miR-31 and cancer-related proinflammation genes. Here we report that treatment of ZD rats with locked nucleic acid (LNA)-modified inhibitor of miR-31 (LNA-antimiR) prevents the development of a precancerous esophageal phenotype. Weanling rats were fed ZD or zinc-sufficient (ZS) diet for 5 weeks. Simultaneously, ZD rats were administered intravenously (twice a week) LNA-antimiR, LNA-scramble miR-31 or the vehicle saline. ZS rats received saline. Compared to ZS rats, LNA-scramble miR-31-treated or saline-treated ZD rats overexpressed miR-31 and displayed a highly proliferative and inflammatory esophageal phenotype. Treatment of ZD rats with LNA-antimiR reduced miR-31 expression in esophageal epithelia and circulating blood by ~60% and reversed the ZD-induced esophageal pathology, as evidenced by a thinned esophageal epithelium with reduced cell proliferation by PCNA immunohistochemistry and increased apoptosis by caspase-3/7 activity. Transcriptome analyses of esophageal epithelia demonstrated derepression of target mRNAs with miR-31 seed sites. In particular, Stk40 (a negative regulator of NF-κ? signaling) was demonstrated to be a bona fide miR-31 target. Using in situ hybridization and immunohistochemistry, miR-31 overexpression in ZD esophageal sections correlated with downregulation of STK40 protein, as well as with upregulation of an NF-κ? p65 - RAGE-S100A9 inflammatory pathway that in turn, was normalized by miR-31 silencing. Thus, silencing miR-31 prevents esophageal neoplasia. Overexpression of miR-31 promotes ESCC initiation by enhancing inflammation via STK40 - NF-κ? signaling. The data indicate that miR-31 may be a promising therapeutic target for improved ESCC diagnosis and prevention. Funding: National Institutes of Health grants U01 CA152758 to CMC and R01CA118560 & R21CA152505 to LYYF.

Citation

Taccioli, C., Chen, H., Garofalo, M., Jiang, Y., Di Leva, G., Alder, H., …Fong, L. Y. Y. (2013). Abstract LB-241: Silencing of microRNA-31 prevents esophageal neoplasia in zinc deficient rats. Cancer Research, 73(8_Supplement), LB-241-LB-241. https://doi.org/10.1158/1538-7445.am2013-lb-241

• Journal Article Type: Conference Paper
• Conference Name: AACR 104th Annual Meeting 2013; Apr 6-10, 2013
• Conference Location: Washington, DC, USA
• Publication Date: Apr 15, 2013
• Deposit Date: Jun 12, 2023
• Journal: Cancer Research
• Print ISSN: 0008-5472
• Electronic ISSN: 1538-7445
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 73
• Issue: 8_Supplement
• Article Number: LB-241
• Pages: LB-241-LB-241
• DOI: https://doi.org/10.1158/1538-7445.am2013-lb-241
• Keywords: Cancer Research; Oncology