miR-373-3p promotes aerobic glycolysis in colon cancer cells by targeting MFN2

Abstract

MicroRNAs (miRNAs) are implicated in the development of cancers and may serve as potential targets for therapy. However, the functions and underlying mechanisms of miRNAs in cancers are not well understood. This work aims to study the role of miR-373-3p in colon cancer cells. We find that the expression of miR-373-3p mimics promotes and the miR-373-3p inhibitor suppresses aerobic glycolysis and proliferation of colon cancer cells. Mechanistically, miR-373-3p inhibits the expression of MFN2, a gene that is known to suppress glycolysis, which leads to the activation of glycolysis and eventually the proliferation of cells. In a nude mouse tumor model, the expression of miR-373-3p in colon cancer cells promotes tumor growth by enhancing lactate formation, which is inhibited by the co-expression of MFN2 in the cells. Administration of the miR-373-3p antagomir blunts in vivo tumor growth by decreasing lactate production. In addition, in human colon cancers, the expression levels of miR-373-3p are increased, while those of MFN2 mRNA are decreased, and the increase of miR-373-3p is associated with the decrease of MFN2 mRNA. Our results reveal a previously unknown function and underlying mechanism of miR-373-3p in the regulation of glycolysis and proliferation in cancer cells and underscore the potential of targeting miR-373-3p for colon cancer treatment.

1. Introduction

MicroRNAs (miRNAs) are a subclass of small noncoding RNAs (ncRNAs). They are single-stranded RNA molecules of approximately 19‒24 nucleotides (nt) that are typically derived from 60- to 110-nt RNA hairpin precursors [1]. miRNAs are transcribed as primary miRNAs (pri-miRNAs), which are subsequently cleaved into precursor miRNAs (pre-miRNAs) and further processed into mature single-stranded ~22-nt miRNAs [2]. The biogenesis of miRNAs involves a complex protein system that includes the RNase III enzymes DROSHA and DICER1 [3]. The classic function of miRNAs is post-transcriptionally repressing expressions of specific target proteins by either promoting mRNA decay or dampening translation [1,4]. Recent studies have demonstrated that miRNAs may also be involved in translational upregulation, epigenetic regulation, and transcriptional activation [5].

miRNAs are involved in biological processes, including cell proliferation, differentiation, and apoptosis [1], and are expressed in distinct spatial and temporal patterns, both during embryonic and postnatal development and in adult tissues [6]. miRNAs have regulatory effects on metabolic enzymes, signaling pathways, and transcription factors involved in glucose and lipid metabolism [7,8]. miRNAs are associated with cancers [9,10] and have been proven to drive or repress tumorigenesis [11]. In cancer cells, miRNAs were found to control the Warburg effect, i.e., aerobic glycolysis [12–14]. Dysregulated miRNAs are associated with the clinical pathological features of many tumors, and they may serve as biomarkers for diagnosis and prognosis and as therapeutic targets for tumors [15–17].

Mitofusin 2 (MFN2) is implicated in cancer development [18]. MFN2 is downregulated in some types of cancer and inhibits cancer cells [19]. Bioinformatics analysis indicated that MFN2 is a promising predictive biomarker and therapeutic target for colon cancer [20]. Ovarian cancer patients with higher MFN2 expression have better survival than those with lower MFN2 expression [21]. Both breast and lung cancer patients with low MFN2 expression are associated with poor prognosis as compared to patients with high MFN2 expression [22]. MFN2 functions to mediate mitochondrial fusion [23] and suppress glycolysis [24–26]. Colon cancer is the third leading cause of death among various cancers and one of the leading causes of cancer death. miRNAs have been shown to be involved in colon cancer development, influencing cancer cell proliferation, apoptosis, metastasis, and angiogenesis [27–29]. To date, the role of miRNAs in the regulation of aerobic glycolysis in colon cancer cells remains largely unclear. Herein, we show that miR-373-3p targets MFN2 to promote aerobic glycolysis and proliferation in colon cancer cells. Targeting miR-373-3p inhibited the proliferation of colon cancer cells in vitro and tumor growth in vivo. Our results revealed a previously unknown function and underlying mechanism of miR-373-3p in colon cancer cells. Our findings also suggest that miR-373-3p may serve as a target for colon cancer treatment.