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- Title
Repression of Esophageal Neoplasia and Inflammatory Signaling by Anti-miR-31 Delivery In Vivo.
- Authors
Taccioli, Cristian; Garofalo, Michela; Hongping Chen; Yubao Jiang; Malagoli Tagliazucchi, Guidantonio; Di Leva, Gianpiero; Alder, Hansjuerg; Fadda, Paolo; Middleton, Justin; Smalley, Karl J.; Selmi, Tommaso; Naidu, Srivatsava; Farber, John L.; Croce, Carlo M.; Fong, Louise Y.; Chen, Hongping; Jiang, Yubao; Tagliazucchi, Guidantonio Malagoli
- Abstract
<bold>Background: </bold>Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined.<bold>Methods: </bold>To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter assay. Cellular proliferation, apoptosis, and expression of inflammation genes were determined by immunoblotting, caspase assays, and immunohistochemistry. The miR-31 promoter in Zn-deficient esophagus was identified by ChIP-seq using an antibody for histone mark H3K4me3. Data were analyzed with t test and analysis of variance. All statistical tests were two-sided.<bold>Results: </bold>In vivo, anti-miR-31 reduced miR-31 overexpression (P = .002) and suppressed the esophageal preneoplasia in Zn-deficient rats. At the same time, the miR-31 target Stk40 was derepressed, thereby inhibiting the STK40-NF-κΒ-controlled inflammatory pathway, with resultant decreased cellular proliferation and activated apoptosis (caspase 3/7 activities, fold change = 10.7, P = .005). This same connection between miR-31 overexpression and STK40/NF-κΒ expression was also documented in human ESCC cell lines. In Zn-deficient esophagus, the miR-31 promoter region and NF-κΒ binding site were activated. Zn replenishment restored the regulation of this genomic region and a normal esophageal phenotype.<bold>Conclusions: </bold>The data define the in vivo signaling pathway underlying interaction of Zn deficiency and miR-31 overexpression in esophageal neoplasia and provide a mechanistic rationale for miR-31 as a therapeutic target for ESCC.
- Subjects
MICRORNA; SQUAMOUS cell carcinoma; ZINC deficiency diseases; OLIGONUCLEOTIDES; IMMUNOHISTOCHEMISTRY
- Publication
JNCI: Journal of the National Cancer Institute, 2015, Vol 107, Issue 11, p1
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djv220