Zinc treatment reverses and anti-Zn-regulated miRs suppress esophageal carcinomas in vivo

Author:

Fong Louise Y.12ORCID,Huebner Kay3,Jing Ruiyan1,Smalley Karl J.2ORCID,Brydges Christopher R.4,Fiehn Oliver4ORCID,Farber John L.1,Croce Carlo M.3ORCID

Affiliation:

1. Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107

2. Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107

3. Department of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210

4. NIH West Coast Metabolomics Center, The Genome Center, University of California, Davis, CA 95616

Abstract

Esophageal squamous cell carcinoma (ESCC) is a deadly disease with few prevention or treatment options. ESCC development in humans and rodents is associated with Zn deficiency (ZD), inflammation, and overexpression of oncogenic microRNAs: miR-31 and miR-21. In a ZD-promoted ESCC rat model with upregulation of these miRs, systemic antimiR-31 suppresses the miR-31-EGLN3/STK40-NF-κB–controlled inflammatory pathway and ESCC. In this model, systemic delivery of Zn-regulated antimiR-31, followed by antimiR-21, restored expression of tumor-suppressor proteins targeted by these specific miRs: STK40/EGLN3 (miR-31), PDCD4 (miR-21), suppressing inflammation, promoting apoptosis, and inhibiting ESCC development. Moreover, ESCC-bearing Zn-deficient (ZD) rats receiving Zn medication showed a 47% decrease in ESCC incidence vs. Zn-untreated controls. Zn treatment eliminated ESCCs by affecting a spectrum of biological processes that included downregulation of expression of the two miRs and miR-31-controlled inflammatory pathway, stimulation of miR-21-PDCD4 axis apoptosis, and reversal of the ESCC metabolome: with decrease in putrescine, increase in glucose, accompanied by downregulation of metabolite enzymes ODC and HK2. Thus, Zn treatment or miR-31/21 silencing are effective therapeutic strategies for ESCC in this rodent model and should be examined in the human counterpart exhibiting the same biological processes.

Funder

HHS | NIH | NCI | Basic Research Laboratory

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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