P31 Role of sesquiterpene lactones against human ovarian cancer

Fadayomi, Idowu Eniafe; Forsyth, Nicholas; Li, Wen-Wu

Abstract

Background:
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.

Methods:
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.

Results:
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.

Conclusions:
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.

Citation

Fadayomi, I. E., Forsyth, N., & Li, W. (2017). P31 Role of sesquiterpene lactones against human ovarian cancer. Biochemical Pharmacology, 139(11), 134-135. https://doi.org/10.1016/j.bcp.2017.06.032

• Journal Article Type: Article
• Publication Date: 2017-09
• Deposit Date: Jun 12, 2023
• Journal: Biochemical Pharmacology
• Print ISSN: 0006-2952
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 139
• Issue: 11
• Pages: 134-135
• DOI: https://doi.org/10.1016/j.bcp.2017.06.032
• Keywords: Pharmacology; Biochemistry; apoptosis; northern blotting; phenotype; polymerase chain reaction; signal transduction; in situ hybridization; immunohistochemistry; inflammation; cell proliferation; diet; binding sites; caspases; cell lines; genes; genome; h