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., Middleton, J., Smalley, K. J., Bottoni, A., Costinean, S., Farber, J. L., Croce, C. M., & Fong, L. Y. Y. Abstract LB-241: Silencing of microRNA-31 prevents esophageal neoplasia in zinc deficient rats. Presented at AACR 104th Annual Meeting 2013; Apr 6-10, 2013, Washington, DC, USA

• Presentation Conference Type: Conference Paper (published)
• Conference Name: AACR 104th Annual Meeting 2013; Apr 6-10, 2013
• 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
• Public URL: https://keele-repository.worktribe.com/output/447005