PLX291299

GSE134442: miR-4711-5p regulates the cancer stemness and cell cycle progression through direct binding to KLF5, MDM2 and TFDP1 in colon cancer cells

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

It is important to establish cancer stem cells (CSCs)-targeted therapy for eradication of cancer. In this study, we searched for candidate microRNAs (miRNAs) by in silico analyses, which inhibit a stem cell-related gene Krppel-like factor 5 (KLF5). After in vitro screening we focused on miR-4711-5p which proved to inhibit cancer stemness and G1-S cell cycle progression. We found by luciferase binding assays that miR-4711-5p directly bound to KLF5, TFDP1 (a heterodimeric partner with E2F family), and MDM2 (one responsible gene for degradation of wild type p53). This miRNA suppressed cell proliferation, migration, and invasion ability in DLD-1 and HCT116 cells as well as the cancer stemness including low reactive oxygen species (ROS) activity, and sphere formation ability. The expressions of stem cell markers, LGR5, CD44v9, and BMI1 also decreased. MiR-4711-5p inhibited the in vivo growth of pre-established DLD-1 xenografts without apparent adverse effect. RNA sequence Analyses indicated that the transition from G1 phase to S phase in cell cycle was disturbed by miR-4711-5p. We indeed found that miR-4711-5p provoked G1 arrest with increase in CDK inhibitor p27KIP1 and/or p21WAF1/CIP1 and decrease in CDK2, 4, 6 and Cyclin D1 protein expression. These changes could be attributed to direct binding of miR-4711-5p to TFDP1. It is also suggested that down-regulation of MDM2 could permit to accumulate the wild type p53 protein in HCT116, leading to drastic induction of the p21WAF1/CIP1 protein and apoptosis. Our data suggest that miR-4711-5p could be a hopeful next generation treatment for CSC-targeted therapy. SOURCE: Daisuke Okuzaki (dokuzaki@biken.osaka-u.ac.jp) - Research institute for microbial diseases, Osaka university