MiR-365a-3p-Mediated Regulation of HELLS/GLUT1 Axis Suppresses Aerobic Glycolysis and Gastric Cancer Growth.

Rui Yang,Limin Han,Yuheng Qiu,Gen Liu,Lulin Wang,Mei Wang

doi:10.3389/fonc.2021.616390

Abstract

Gastric cancer (GC) is a common and invasive malignancy, which lacks effective treatment and is the third main reason of cancer death. Metabolic reprogramming is one of the main reasons that GC is difficult to treat in various environments. Particularly, abnormal glycolytic activity is the most common way of metabolism reprogramming in cancer cells. Numerous studies have shown that microRNAs play important roles in reprogramming glucose metabolism. Here, we found a microRNA-miR-365a-3p, was significantly downregulated in GC according to bioinformatics analysis. Low expression of miR-365a-3p correlated with poor prognosis of GC patients. Overexpression of miR-365a-3p in GC cells significantly inhibited cell proliferation by inducing cell cycle arrest at G1 phase. Notably, miR-365a-3p induced downregulation of HELLS through binding to its 3′ untranslated region (UTR). Additionally, we found that miR-365a-3p suppressed aerobic glycolysis by inhibiting HELLS/GLUT1 axis. Lastly, we shown that overexpression of miR-365a-3p significantly inhibited tumor growth in nude mice. Conversely, Reconstituted the expression of HELLS rescued the suppressive effects of miR-365a-3p. Our data collectively indicated that miR-365a-3p functioned as a tumor suppressor in GC through downregulating HELLS. Therefore, targeting of the novel miR-365a-3p/HELLS axis could be a potentially effective therapeutic approach for GC.

Highlights

Gastric cancer (GC) is a common and invasive malignancy, which lacks effective treatment and is the third main reason of cancer death [1, 2]
MiR-365a-3p Was Low Expressed in GC and Low Expression of miR-365a-3p Correlates With Poor Patient Prognosis
We found that miR-365a-3p might play an anti-tumor role in GC by targeting HELLS

Summary

Introduction

Gastric cancer (GC) is a common and invasive malignancy, which lacks effective treatment and is the third main reason of cancer death [1, 2]. MiR-365a-3p-HELLS Axis in Gastric Cancer prognosis of advanced patients remains poor [4, 5]. There is an urgent need to reveal the underlying mechanisms of gastric carcinogenesis at molecular events, to improve the life quality of GC patients. Epigenetic changes have been identified that play crucial roles in carcinogenesis, among them, microRNAs (miRNAs) have attracted more attention. MiRNAs factor is the key to the regulation of gene expression, to participate in regulation of cell hyperplasia, apoptosis and metabolism, the development of nervous system diseases, cardiovascular disease and cancer [8,9,10]. Multiple miRNAs including miR-7, miR409-3p, miR-221 and miR-155 have been identified as important regulators in GC [11,12,13,14]. Previous studies have shown that miR-365a-3p is downregulated in some cancers [15,16,17], but its biological functions in GC are largely unknown

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Conclusion