MiR-149-3p promotes the cisplatin resistance and EMT in ovarian cancer through downregulating TIMP2 and CDKN1A

Jin Wang,Lingxia Liu

doi:10.1186/s13048-021-00919-5

Abstract

BackgroundOvarian cancer (OC), a kind of gynecological cancer, is characterized by high mortality rate, with microRNAs (miRNAs) playing essential roles in it. However, the clinical significance of miRNAs and their molecular mechanisms in OC are mostly unknown.MethodsmiR-149-3p expression was predicted through Gene Expression Omnibus (GEO) data in OC and confirmed by q-PCR in various OC cells and tissues from patients with different clinical characteristics. Moreover, its roles in terms of proliferation, migration and invasion were measured by CCK-8, colony formation, wound healing and transwell assays in OC cells including cisplatin-resistant and cisplatin-sensitive cells. And its effect on epithelial-mesenchymal transition was also assessed through detecting related protein expression. Additionally, its potential targets were verified by dual luciferase assay and Ago-RIP assay. Finally, its oncogenic functions were explored in vivo.ResultsIn data from GSE79943, GSE131790, and TCGA, miR-149-3p was found to be highly expressed in OC tissues and associated with poor survival. In metastasis and chemoresistant tissues and cisplatin-resistant OC cells, its high expression was confirmed. In terms of tumorigenic effects, miR-149-3p knockdown in cisplatin-resistant OC cells inhibited its cisplatin resistance and other malignant phenotypes, while miR-149-3p overexpression in cisplatin-resistant OC cells led to contrary results. Mechanistically, miR-149-3p targeted 3’UTR of CDKN1A and TIMP2 to function as an oncogenic miRNA.ConclusionIn brief, miR-149-3p promoted cisplatin resistance and EMT in OC by downregulating CDKN1A and TIMP2, which might provide a potential therapeutic target for OC treatment.

Highlights

Ovarian cancer (OC), a kind of gynecological cancer, is characterized by high mortality rate, with microRNAs playing essential roles in it
The Cancer Genome Atlas (TCGA) data showed that miR-149-3p was highly expressed in OC with tumor residual compared miR‐149‐3p inhibitor suppressed cisplatin resistance in cisplatin‐resistant OC cells To investigate the resistance of OC cells to cisplatin, SKOV3, SKOV3/DDP, A2780 and A2780/DDP cells were treated with different concentrations of cisplatin and detected by CCK-8
We found that TIMP2 and cyclin-dependent kinase inhibitor 1A (CDKN1A) were lowly expressed in cases with metastasis and chemosensitivity (Fig. 4C-D)

Summary

Introduction

Ovarian cancer (OC), a kind of gynecological cancer, is characterized by high mortality rate, with microRNAs (miRNAs) playing essential roles in it. The clinical significance of miRNAs and their molecular mechanisms in OC are mostly unknown. The incidence of ovarian cancer (OC) ranks the fourth in gynecological malignancies, and the mortality ranks the second in gynecological cancers [1]. Since 60% ~ 70% of patients are diagnosed with advanced stage, about 80% of patients will relapse in the first five years [2]. Treatment advances and outcomes for OC have been. The emergence of microRNAs (miRNAs), special type of non-coding RNAs (ncRNAs), has attracted attention for more than two decades. MiRNAs, consisting of about 20 nucleotides [4], have important regulatory functions.

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