MicroRNA-92a-3p Enhances Cisplatin Resistance by Regulating Krüppel-Like Factor 4-Mediated Cell Apoptosis and Epithelial-to-Mesenchymal Transition in Cervical Cancer.

Jing Yang,Jing Hai,Mengjie Zhang,Xuecai Dong,Shufeng Duan

doi:10.3389/fphar.2021.783213

Jing Yang, Jing Hai + Show 3 more

Open Access

https://doi.org/10.3389/fphar.2021.783213

Copy DOI

Abstract

Recent studies have confirmed the existence and key roles of microRNA (miRNAs) in cancer drug resistance, including cervical cancer (CC). The present study aims to establish a novel role for miR-92a-3p and its associated gene networks in cisplatin (DDP) resistance of CC. First, the disparities in miRNA expression between CC tissues and adjacent normal tissues were screened based on GSE19611 microarray data that retrieved from Gene Expression Omnibus (GEO), and we identified several miRs that were significantly downregulated or upregulated in CC tissues including miR-92a-3p. Moreover, miR-92a-3p was significantly up-regulated in DDP-resistant cells and was the most differently expressed miRNA. Functionally, knockdown of miR-92a-3p increased the sensitivity of DDP-resistant cells to DDP via inhibiting cell proliferation, migration and invasion, and promoting apoptosis. Conversely, overexpression of miR-92a-3p significantly induced DDP resistance in CC parental cells including HeLa and SiHa cells. Moreover, Krüppel-like factor 4 (KLF4) was identified as a direct target of miR-92a-3p, and an obvious inverse correlation was observed between the expression of miR-92a-3p and KLF4 in 40 pairs of cancer tissues. Furthermore, KLF4 knockdown reversed the promoting effect of miR-92a-3p inhibition on DDP sensitivity in DDP-resistant CC cells. Besides, high expression of miR-92a-3p was associated with DDP resistance, as well as a short overall survival in clinic. Taken together, these findings provide important evidence that miR-92a-3p targets KLF4 and is significant in DDP resistance in CC, indicating that miR-92a-3p may be an attractive target to increase DDP sensitivity in clinical CC treatment.

Highlights

Cervical cancer (CC) is the fourth common cancer among women, which accounts for approximately 7.5% of the total cancer deaths worldwide (Chatterjee et al, 2019)
We found that miR-92a-3p was upregulated in cisplatin (DDP)-resistant CC cells
MiR-92a-3p inhibition increased the sensitivity of DDP-resistant CC cells to DDP by directly targeting Krüppel-like factor 4 (KLF4)

Summary

Introduction

Cervical cancer (CC) is the fourth common cancer among women, which accounts for approximately 7.5% of the total cancer deaths worldwide (Chatterjee et al, 2019). Despite significant improvement in therapy for preventing CC, annually, approximately 500,000 women develop CC worldwide, and about 200,000 die of this disease (Diaz-Padilla et al, 2013). MicroRNA-92a-3p Enhances Cisplatin Resistance chemoradiotherapy is considered as the standard treatment for patients with advanced/recurrent cervical cancer. The clinical usage of cisplatin is limited due to the acquisition of chemotherapy resistance in CC (Amable, 2016). Studies of the mechanism and reliable prognostic markers to overcome cisplatin resistance are needed to improve outcomes in patients with CC. Cisplatin (DDP), a platinum-based anticancer agent, is clinically proven to have significant efficacy in different types of cancers including CC (Lorusso et al, 2014). It is estimated that approximately 50% of all patients with cancer will be treated with DDP in their anticancer therapies. Previous studies suggest that DDP resistance can result from epigenetic changes at molecular and cellular levels, including up- or down-regulated expression of microRNA (miRNA) (Croce, 2009)

Methods

Results

Conclusion