Leptin modulated microRNA-628-5p targets Jagged-1 and inhibits prostate cancer hallmarks.

Abstract

MicroRNAs (miRNAs) are single-stranded non-coding RNA molecules that play a regulatory role in gene expression and cancer cell signaling. We previously identified miR-628-5p (miR-628) as a potential biomarker in serum samples from men with prostate cancer (PCa) (Srivastava et al. in Tumour Biol 35:4867-4873, 10.1007/s13277-014-1638-1, 2014). This study examined the detailed cellular phenotypes and pathways regulated by miR-628 in PCa cells. Since obesity is a significant risk factor for PCa, and there is a correlation between levels of the obesity-associated hormone leptin and PCa development, here we investigated the functional relationship between leptin and miR-628 regulation in PCa. We demonstrated that exposure to leptin downregulated the expression of miR-628 and increased cell proliferation/migration in PCa cells. We next studied the effects on cancer-related phenotypes in PCa cells after altering miR-628 expression levels. Enforced expression of miR-628 in PCa cells inhibited cell proliferation, reduced PCa cell survival/migration/invasion/spheroid formation, and decreased markers of cell stemness. Mechanistically, miR-628 binds with the JAG1-3'UTR and inhibits the expression of Jagged-1 (JAG1). JAG1 inhibition by miR-628 downregulated Notch signaling, decreased the expression of Snail/Slug, and modulated epithelial-mesenchymal transition and invasiveness in PC3 cells. Furthermore, expression of miR-628 in PCa cells increased sensitivity towards the drugs enzalutamide and docetaxel by induction of cell apoptosis. Collectively our data suggest that miR-628 is a key regulator of PCa carcinogenesis and is modulated by leptin, offering a novel therapeutic opportunity to inhibit the growth of advanced PCa.

• Authors: Leslimar Rios-Colon, Juliet Chijioke, Suryakant Niture, Zainab Afzal, Qi Qi, Anvesha Srivastava, Malathi Ramalinga, Habib Kedir, Patrice Cagle, Elena Arthur, Mitu Sharma, John Moore, Gagan Deep, Simeng Suy, Sean P Collins, Deepak Kumar
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 10073 (06 16 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35710817 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2022. The Author(s).

Chemical References

• Jagged-1 Protein
• Leptin
• MIRN628 microRNA, human
• MicroRNAs

Topics

• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Jagged-1 Protein (genetics, metabolism)
• Leptin (genetics, metabolism)
• Male
• MicroRNAs (genetics, metabolism)
• Obesity (genetics)
• Prostatic Neoplasms (pathology)