The Role of the SOX9/lncRNA ANXA2P2/miR-361-3p/SOX9 Regulatory Loop in Cervical Cancer Cell Growth and Resistance to Cisplatin.

Shasha He,Wei Xiong,Yeqian Feng,Jin-an Ma,Xianling Liu,Wen Zou,Jingjing Wang,Guiyuan Li,Yangchun Xie

doi:10.3389/fonc.2021.784525

Abstract

Cervical cancer is a highly prevalent female malignancy. Presently, cisplatin (DDP) is a first-line agent for cervical cancer chemotherapy. However, its curative effect is limited because of chemo-resistance. It has been previously reported that SOX9 targeted and activated oncogenic genes, enhancing cervical cancer cell resistance to DDP. The effects of the SOX9/lncRNA ANXA2P2/miR-361-3p/SOX9 regulatory loop on cervical cancer cell growth and resistance to DDP have been demonstrated. miR-361-3p expression was decreased in DDP-resistant cervical cancer cells and tissues. Moreover, miR-361-3p overexpression inhibited the growth of resistant cervical cancer cells and the resistance to DDP, whereas miR-361-3p inhibition exerted opposite effects. miR-361-3p inhibited SOX9 expression through binding; the effects of miR-361-3p inhibition were partially reversed by SOX9 knockdown. LncRNA ANXA2P2 expression was elevated in DDP-resistant cervical cancer cells and tissues. LncRNA ANXA2P2 inhibited miR-361-3p expression by binding, thereby upregulating SOX9. LncRNA ANXA2P2 knockdown inhibited DDP-resistant cervical cancer cell growth and resistance to DDP, whereas the effects of lncRNA ANXA2P2 knockdown were partially reversed by miR-361-3p inhibition. SOX9 expression was elevated in DDP-resistant cervical cancer cells and tissues, and SOX9 activated lncRNA ANXA2P2 transcription by binding. Collectively, SOX9, lncRNA ANXA2P2, and miR-361-3p form a regulatory loop, modulating DDP-resistant cervical cancer cell growth and response to DDP treatment.

Highlights

Cervical cancer is a widespread female malignancy with high incidence and results in over 300,000 yearly fatalities worldwide [1, 2]
The specific functions of the SOX9/Long non-coding RNAs (lncRNAs) ANXA2P2/miR361-3p/SOX9 regulatory loop on the growth and DDP-resistance of cervical cancer cells were demonstrated (Figure 8). miR-3613p expression was underexpressed in DDP-resistant cervical cancer cells and tissues. miR-361-3p overexpression inhibited DDP-resistant cervical cancer cell growth and resistance to DDP, whereas miR-361-3p inhibition exerted opposite effects. miR361-3p inhibited SOX9 expression through binding; the effects of miR-361-3p inhibition on DDP-resistant cervical cancer cells were partially reversed by SOX9 knockdown
LncRNA ANXA2P2 expression was elevated in DDP-resistant cervical cancer cells and tissues

Summary

Introduction

Cervical cancer is a widespread female malignancy with high incidence and results in over 300,000 yearly fatalities worldwide [1, 2]. Our group reported miR-130a [9, 10] and miR-21 [11] modulating cervical cancer cell growth and resistance to DDP through targeting CTR1 or PTEN. There are more miRNAs that have been reported as multifaceted players regulating cancer aggressiveness and tumor microenvironment formation, such as miR-361. MiR-361-3p is often reduced or lost in numerous kinds of malignancies and participates in tumor growth, epithelial–mesenchymal transition (EMT), distant migration, chemo- or radio-resistance, glycolysis, angiogenesis, and inflammation by inhibiting the expression of its target genes [12,13,14,15,16]. Wang et al [15] regarded miR-3613p as an anti-tumor miRNA in cervical cancer-inhibiting cancer cell growth and invasion, its role, targets, and mechanism in cervical cancer resistance to DDP are still unclear

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