1. Leptin modulated microRNA-628-5p targets Jagged-1 and inhibits prostate cancer hallmarks.
- Author
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Rios-Colon L, Chijioke J, Niture S, Afzal Z, Qi Q, Srivastava A, Ramalinga M, Kedir H, Cagle P, Arthur E, Sharma M, Moore J, Deep G, Suy S, Collins SP, and Kumar D
- Subjects
- Cell Line, Tumor, Cell Movement genetics, Cell Proliferation genetics, Gene Expression Regulation, Neoplastic, Humans, Jagged-1 Protein genetics, Jagged-1 Protein metabolism, Leptin genetics, Leptin metabolism, Male, Obesity genetics, MicroRNAs genetics, MicroRNAs metabolism, Prostatic Neoplasms pathology
- 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., (© 2022. The Author(s).)
- Published
- 2022
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