MicroRNA-498 disturbs the occurrence and aggression of colon cancer through targeting MDM2 to mediate PPARγ ubiquitination

Life Sci. 2021 Feb 19;277:119225. doi: 10.1016/j.lfs.2021.119225. Online ahead of print.

Abstract

Objective: MicroRNA (miR)-498 is indicative of diagnostic and prognostic significance in colon cancer (CC). On the basis of that, this study is initiated from miR-498, combined with mouse double minute 2 (MDM2)/peroxisome proliferator-activated receptor γ (PPARγ) ubiquitination axis to have an insight into CC progression.

Methods: CC tissues and their adjacent tissues were harvested to determine miR-498, MDM2 and PPARγ expression. The interactions among these three factors were identified. The screened human CC cells were transfected with miR-498/MDM2-related sequences, followed by detection of the biological behaviors of CC cells. Xenografted tumors were taken to validate cell experimental outcomes. Bioinformatics and dual-luciferase report analysis verified the targeting relationship between miR-498 and MDM2. The relation between MDM2 and PPARγ was identified by immunoprecipitation and in vivo deubiquitination.

Results: Down-regulated miR-498 and PPARγ and up-regulated MDM2 were exhibited in CC. miR-498 targeted MDM2 while MDM2 mediated PPARγ ubiquitination. Elevated miR-498 or reduced MDM2 impaired cell viability, colony-forming, migratory and invasive activities and enhanced apoptosis in CC. Elevated MDM2 abolished the effects of up-regulated miR-498 on the biological behaviors of CC cells. Elevated miR-498 or reduced MDM2 depressed tumorigenic ability of CC cells in mice.

Conclusion: It is conclusive that restoring miR-498 depresses MDM2 to modify PPARγ ubiquitination, thereby disturbing the tumorigenesis of CC. This work constructs the base for exploring novel agents in treating CC.

Keywords: Colon cancer; MicroRNA-498; Mouse double minute 2; Peroxisome proliferator-activated receptor γ; Tumorigenesis; Ubiquitination.