microRNA-155 positively regulates glucose metabolism via PIK3R1-FOXO3a-cMYC axis in breast cancer

• Published in: Oncogene Vol. 37; no. 22; pp. 2982 - 2991
• Main Authors: Kim, Sinae, Lee, Eunji, Jung, Jaeyun, Lee, Jong Won, Kim, Hee Jung, Kim, Jisun, Yoo, Hyun ju, Lee, Hee Jin, Chae, Sun Young, Jeon, Sang Min, Son, Byung Ho, Gong, Gyungyup, Sharan, Shyam K, Chang, Suhwan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2018; Nature Publishing Group
• Subjects: 13; 3' Untranslated Regions; 38/77; 631/67/1347; 631/67/2327; 631/67/395; 631/67/70; 64; 64/60; 82/58; 96; 96/109; 96/31; 96/95; AKT protein; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Care and treatment; Carrier proteins; Cell Biology; Cell Line, Tumor; Chromatography, Liquid; Development and progression; Female; Forkhead Box Protein O3 - genetics; FOXO3 protein; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic regulation; Glucose; Glucose - metabolism; Glycolysis; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; MCF-7 Cells; Medicine; Medicine & Public Health; Metabolism; Mice; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Neoplasm Transplantation; Oncology; Phosphatidylinositol 3-Kinases - genetics; Proto-Oncogene Proteins c-myc - genetics; Signal Transduction; Tandem Mass Spectrometry; Tumorigenesis; South Korea
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0124-4

MicroRNA is an endogenous, small RNA controlling multiple target genes and playing roles in various biological processes including tumorigenesis. Here, we addressed the function of miR-155 using LC-MS/MS-based metabolic profiling of miR-155 deficient breast cancer cells. Our results revealed the loss of miR-155 hampers glucose uptake and glycolysis, via the down-regulation of glucose transporters and metabolic enzymes including HK2, PKM2, and LDHA. We showed this is due to the down-regulation of cMYC, controlled through phosphoinositide-3-kinase regulatory subunit alpha (PIK3R1)-PDK1/AKT-FOXO3a pathway. UTR analysis of the PIK3R1 and FOXO3a indicated miR-155 directly represses these genes. A stable expression of miR-155 in patient-derived cells (PDCs) showed activated glucose metabolism whereas a stable inhibition of miR-155 reduced in vivo tumor growth with retarded glucose metabolism. Furthermore, analysis of 50 triple-negative breast cancer (TNBC) specimens and specific uptake value (SUV) of PET images revealed a positive correlation between miR-155 level and glucose usage in human breast tumors via PIK3R1-PDK/AKT-FOXO3a-cMYC axis. Collectively, these data demonstrate the miR-155 is a key regulator of glucose metabolism in breast cancer.