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

被引:111
作者
Kim, Sinae [1 ]
Lee, Eunji [1 ]
Jung, Jaeyun [1 ]
Lee, Jong Won [2 ]
Kim, Hee Jung [2 ]
Kim, Jisun [2 ]
Yoo, Hyun ju [3 ]
Lee, Hee Jin [4 ]
Chae, Sun Young [5 ]
Jeon, Sang Min [6 ,7 ]
Son, Byung Ho [2 ]
Gong, Gyungyup [4 ]
Sharan, Shyam K. [8 ]
Chang, Suhwan [1 ]
机构
[1] Univ Ulsan, Coll Med, Dept Biomed Sci, Seoul 05505, South Korea
[2] Asan Med Ctr, Dept Surg, Seoul 05505, South Korea
[3] Univ Ulsan, Coll Med, Dept Convergence Med, Seoul 05505, South Korea
[4] Asan Med Ctr, Dept Pathol, Seoul 05505, South Korea
[5] Asan Med Ctr, Dept Nucl Med, Seoul 05505, South Korea
[6] Ajou Univ, Coll Pharm, Suwon 16499, South Korea
[7] Ajou Univ, Inst Pharmaceut Sci & Technol, Suwon 16499, South Korea
[8] Frederick Natl Lab, Mouse Canc Genet Program, Frederick, MD 21702 USA
关键词
GENE-EXPRESSION; MIR-155; REVEALS; CELLS; TARGETS; GROWTH; FOXO3A; BRCA1; MYC;
D O I
10.1038/s41388-018-0124-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2982 / 2991
页数:10
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