MiR-34a-5p enhances the sensitivity of cervical cancer cells to oxaliplatin chemotherapy via targeting MDM4

Lirong Cao,Pei He,Shixiong Gong,Xiaoli Liu,Yanqin Lou

doi:10.31083/j.ceog4902054

Abstract

Background: Cervical cancer is a common gynecologic malignancy worldwide, mainly developing in women aged about 50 years old. Currently, oxaliplatin (L-OHP) was widely used as a first-line chemotherapeutic drug to treat various tumors, including cervical cancer. The emergence of L-OHP resistance during chemotherapy has largely limited the clinical efficacy of chemotherapy. Numerous studies have demonstrated that abnormal expression of microRNAs (miRNAs) was associated with tumorigenesis and the development of cancer drug resistance. Methods: miR-34a-5p and Murine Double Minute 4 (MDM4) in cervical cancer cells was detected via RT-qPCR and Western blot assay. Cell proliferation and apoptosis were observed via ov-MDM4 and si-MDM4, Cell counting kit (CCK)-8 and flow cytometry analysis after transfection with miR-34a-5p inhibitor, miR-34a-5p mimics, respectively. Dual-luciferase reporter assay was utilized to confirm the associativity between miR-34a-5p and MDM4. Results: miR-34a-5p was significantly down-regulated whereas MDM4 was increased in cervical cancer tumor tissues and cells. Compared with Hela cells, miR-34a-5p was further decreased and MDM4 was elevated in Hela/L-OHP cells. miR-34a-5p significantly inhibited Hela/L-OHP cell viability and promoted apoptosis. Similar to the effects of miR-34a-5p, MDM4 knockdown inhibited Hela/L-OHP cell proliferation, but induced apoptosis. miR-34a-5p directly targeted MDM4 and could improve sensitivity of cervical cancer cells to L-OHP chemosensitivity by targeting MDM4 expression in vitro. Conclusions: miR-34a-5p can improve sensitivity of cervical cancer cells to L-OHP chemosensitivity, serving as a potential curative target for cervical cancer chemotherapy.

Highlights

Cervical cancer is a common malignancy in women, of which squamous cell carcinoma accounted for about 85%, adenocarcinoma for about 10–15%, and squamous adenocarcinoma for 3% [1]
We found that the Murine Double Minute 4 (MDM4) level was gradually increased after adding L-OHP concentration in a dose-dependent manner (Fig. 3D)
The molecular mechanisms of chemotherapeutic drug resistance are complex and diverse, among which abnormal miRNAs expression is closely relative to tumorigenesis and drug resistance

Summary

Introduction

Cervical cancer is a common malignancy in women, of which squamous cell carcinoma accounted for about 85%, adenocarcinoma for about 10–15%, and squamous adenocarcinoma for 3% [1]. Radiotherapy, as well as chemotherapy are the three main treatments for cervical cancer [3]. Oxaliplatin (L-OHP) was widely used as a first-line chemotherapeutic drug to treat various tumors, including cervical cancer. Methods: miR-34a-5p and Murine Double Minute 4 (MDM4) in cervical cancer cells was detected via RTqPCR and Western blot assay. Results: miR-34a-5p was significantly down-regulated whereas MDM4 was increased in cervical cancer tumor tissues and cells. Similar to the effects of miR-34a-5p, MDM4 knockdown inhibited Hela/L-OHP cell proliferation, but induced apoptosis. MiR-34a-5p directly targeted MDM4 and could improve sensitivity of cervical cancer cells to L-OHP chemosensitivity by targeting MDM4 expression in vitro. Conclusions: miR-34a-5p can improve sensitivity of cervical cancer cells to L-OHP chemosensitivity, serving as a potential curative target for cervical cancer chemotherapy

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