Abstract
Reprogrammed energy metabolism, especially the Warburg effect (aerobic glycolysis), is an emerging hallmark of cancer. Different from other breast cancer subtypes, triple-negative breast cancer (TNBC) exhibits high metabolic remodeling, increased aggressiveness and lack of targeted therapies. MicroRNAs (miRNA) are essential to TNBC malignant phenotypes. However, little is known about the contribution of miRNA to aerobic glycolysis in TNBC. Through an integrated analysis and functional verification, we reported that several miRNAs significantly correlates to the Warburg effect in TNBC, including miR-210-3p, miR-105-5p, and miR-767-5p. Ectopic expression of miR-210-3p enhanced glucose uptake, lactate production, extracellular acidification rate, colony formation ability, and reduced serum starvation-induced cell apoptosis. Moreover, GPD1L and CYGB were identified as two functional mediators of miR-210-3p in TNBC. Mechanistically, miR-210-3p targeted GPD1L to maintain HIF-1α stabilization and suppressed p53 activity via CYGB. Ultimately, miR-210-3p facilitated aerobic glycolysis through modulating the downstream glycolytic genes of HIF-1α and p53. Taken together, our results decipher miRNAs that regulate aerobic glycolysis and uncover that miR-210-3p specifically contributes to the Warburg effect in TNBC.
Highlights
Breast cancer is one of the most common malignancies in women across nations and races
To identify which miRNAs contribute to the glycolytic phenotype in triple-negative breast cancer (TNBC), data from triple-negative breast invasive carcinoma patient samples were acquired from The Cancer Genome Atlas (TCGA) and stratified into high glycolysis group (n = 57) or low glycolysis group (n = 56) based on a glycolysis score generated from expression of 10 known glycolytic components (Supplementary Table 1)
We identified that 311 miRNAs were differentially expressed in TNBC tissues compared with their normal counterparts (Fig. 1b)
Summary
Breast cancer is one of the most common malignancies in women across nations and races. The expression status of progesterone receptor, estrogen receptor, and human epidermal growth factor receptor 2 (HER2, overexpression and/or amplification) is of great importance for the management of breast cancer patients. Effective tailored therapies have been developed for breast cancers positive of hormone receptor or HER2 expression[1]. A cancer cell exhibits glycolysis instead of oxidative phosphorylation even in the presence of oxygen, a phenomenon called aerobic glycolysis, known as Warburg effect. Emerging evidence reveals that glycolysis can be hijacked by cancer cells to promote survival, growth, metastasis, stemness, drug resistance, long-term maintenance, and immune evasion[5,6,7]. Several studies have well documented the transcriptional regulators of aerobic glycolysis in cancers, such as HIF-1α, cMYC, p53, FOXK1/2, and SIX15,8–12. Little is known about the regulatory mechanism of aerobic glycolysis at the post-transcriptional level, such as microRNA (miRNA)
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