LINC00337 Regulates KLF5 and Maintains Stem-Cell Like Traits of Cervical Cancer Cells by Modulating miR-145.

Qi Han,Wenjin Wu,Yulan Cui

doi:10.3389/fonc.2020.01433

Abstract

Accumulating literature and evidence has highlighted the cancer stem-like cell (CSC) model as a cellular mechanism responsible for the phenotypic heterogeneity observed in various types of cancers, including cervical cancer. Long non-coding RNAs (lncRNAs) have been implicated in the retention of stem cell-like traits in cancer cells. However, the role of lncRNAs in the acquisition and maintenance of CSCs in cervical cancer remains largely unknown. Hence, the current study identified that LINC00337 knockdown diminished the CSC-like properties of CD44+/CD24low/−SFCs, evidenced by a decline in the generation of tumorospheres and colonies, a reduction in multi-drug resistance gene-1 (MDR-1), Nanog, Sox2, and Oct4 expression, along with an enhancement in cell apoptosis. RNA pull-down assays and RNA immunoprecipitation revealed the role of LINC00337 as a competing endogenous RNA (ceRNA) of microRNA-145 (miR-145). Furthermore, the miR-145 mRNA target, Kruppel-like factor 5 (KLF5), was decreased in CD44+/CD24low/−SFCs upon LINC00337 knockdown. The in vitro results were reproduced in in vivo studies, which provided verification attesting that LINC00337 knockdown attenuated the tumorigenicity of CD44+/CD24low/−SFCs in nude mice. Taken together, the key findings of the current study demonstrate that LINC00337 acts as an oncogenic lncRNA in cervical cancer and exerts its influence on the expression of KLF5 and the maintenance of cancer stem cell-like properties by means of downregulating miR-145.

Highlights

Cervical cancer ranks as the second major gynecological malignancy, with studies suggesting that over half a million women worldwide affected, contributing to an estimated global and annual death toll of more than 300,000 women [1]
These findings provided evidence verifying that CD44+/CD24low/−sphere-forming cells (SFCs) exhibit cancer stem-like cell (CSC)-like traits and LINC00337 which warranted further investigated as a critical governor of cancer stem cell generation and the maintenance of cancer stem cell characteristics in cervical cancer cells
Our findings suggest that LINC00337 knockdown leads to Kruppel like factor 5 (KLF5) inhibition and impairs the maintenance of CSC-like properties of CD44+/CD24low/−SFCs by regulating miR-145

Summary

Introduction

Cervical cancer ranks as the second major gynecological malignancy, with studies suggesting that over half a million women worldwide affected, contributing to an estimated global and annual death toll of more than 300,000 women [1]. Cumulative evidence over the past few years has indicated that non-coding RNAs play a critical role as regulators in a wide array of cancers including cervical cancer, which highlights the urgent need to identify novel biomarkers capable of aiding in the control of disease progression [6]. MicroRNAs (miRNAs) represent endogenously expressed small RNAs that have been underlined as either tumor suppressors or oncogenes serving as posttranscriptional mediators of mRNA expression in recent years [9]. Kruppel like factor 5 (KLF5) was previously demonstrated as a target gene of miR-145 in the study of Cheng et al [12]. The current study aimed to identify the effects associated with the LINC00337, miR-145, and KLF5 on the behaviors of CSCs in cervical cancer. We subsequently further demonstrated that LINC00337 is upregulated in CD44+/CD24low/−SFCs and LINC00337 depletion reduces CSC-like properties of CD44+/CD24low/−SFCs

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Conclusion