MiR-570 inhibits cell proliferation and glucose metabolism by targeting IRS1 and IRS2 in human chronic myelogenous leukemia

Document Type : Original Article

Authors

1 Department of Blood Transfusion, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China

2 Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China

3 Department of Ultrasonography, Harbin medical university cancer hospital, Harbin, Heilongjiang 150081, China

Abstract

Objective(s): Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disorder characterized by the accumulation of myeloid cells with a chromosomal translocation known as the Philadelphia chromosome. In this study, we investigated the roles of miR-570 in CML development.
Materials and Methods: Expression of miR-570 in CML samples and cell lines was determined by qRT-PCR. Glucose uptake and ATP concentration detection assays were used to analyze cell glucose metabolism. MTT and western blot assays were performed for cell proliferation and apoptosis, respectively. The targets of miR-570 were predicted by bioinformatics and confirmed using luciferase activity, qRT-PCR and western blot assays.
Results: The expression levels of miR-570 were significantly reduced in CML clinical samples and cells. Overexpression of miR-570 inhibited cell proliferation, promoted apoptosis, and suppressed glucose metabolism in CML cells. Insulin receptor substrates (IRS) 1 and IRS2 were identified as direct targets of miR-570. IRS1 or IRS2 were knocked down in K562 cells.Loss of IRS1/2 expression led to suppressed cell proliferation, elevated apoptosis, and decreased glucose metabolism in CML cells, which is consistent with their roles as miR-570 targets.
Conclusion: MiR-570 directly targeted IRS1 and IRS2 in CML, suppressing cell proliferation and glucose metabolism. MiR-570 may provide a strategy for CML therapy.

Keywords


1. Nowell PC. The minute chromosome (Phl) in chronic granulocytic leukemia. Blut 1962;  8: 65-66.
2.  Siegel RL, Miller K D, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;  65: 5-29.
3.  McWhirter JR, Galasso DL, Wang JY. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol 1993; 13: 7587-7595.
4.  Winter J, Jung S, Keller S, Gregory RI, Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell  2009; 11: 228-234.
5.  Lin S, Gregory RI. MicroRNA biogenesis pathways in cancer. Nat Rev  Cancer 2015; 15: 321-333.
6.  Hershkovitz-Rokah O, Modai S, Pasmanik-Chor M, Toren A, Shomron N, Raanani P, et al. Restoration of miR-424 suppresses BCR-ABL activity and sensitizes CML cells to imatinib treatment. Cancer Lett  2015; 360:245-256.
7. Yang P, Ni F, Deng RQ, Qiang G, Zhao H, Yang MZ, et al. MiR-362-5p promotes the malignancy of chronic myelocytic leukaemia via down-regulation of GADD45alpha. Mol Cancer 2015; 14:190.
8. Wang W, Li F, Mao Y, Zhou H, Sun J, Li R, et al. A miR-570 binding site polymorphism in the B7-H1 gene is associated with the risk of gastric adenocarcinoma. Hum Genet 2013; 132:641-648.
9. Guo W, Tan W, Liu S, Huang X, Lin J, Liang R, et al.  MiR-570 inhibited the cell proliferation and invasion through directly targeting B7-H1 in hepatocellular carcinoma. Tumour Biol 2015; 36:9049-9057.
10. Tong XD, Liu TQ, Wang GB, Zhang CL, Liu HX. MicroRNA-570 promotes lung carcinoma proliferation through targeting tumor suppressor KLF9. Int J Clin Exp Pathol 2015;  8: 2829-2834.
11.  Ramirez CM, Goedeke L, Rotllan N, Yoon JH, Cirera-Salinas D, Mattison J A, et al. MicroRNA 33 regulates glucose metabolism. Mol Cell Biol 2013;  33: 2891-2902.
12.  Wang LS, Li L, Chu S, Shiang KD, Li M, Sun HY, et al. MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors. Blood 2015; 125:1302-1313.
13.  Racil Z, Razga F, Drapalova J, Buresova L, Zackova D, Palackova M, et al.  Mechanism of impaired glucose metabolism during nilotinib therapy in patients with chronic myelogenous leukemia. Haematologica 2013; 98:e124-126.
14. Dearth RK, Cui X, Kim HJ, Hadsell DL, Lee AV. Oncogenic transformation by the signaling adaptor proteins insulin receptor substrate (IRS)-1 and IRS-2. Cell Cycle 2007; 6:705-713.
15. Geng Y, Ju Y, Ren F, Qiu Y, Tomita Y, Tomoeda M, et al. Insulin receptor substrate 1/2 (IRS1/2) regulates Wnt/beta-catenin signaling through blocking autophagic degradation of dishevelled2.  J Biol Chem 2014; 289:11230-11241.
16. Reuveni H, Flashner-Abramson E, Steiner L, Makedonski K, Song R, Shir A, et al.  Therapeutic destruction of insulin receptor substrates for cancer treatment. Cancer Res 2013; 73:4383-4394.
17. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 2006; 7: 85-96.
18. Bommer GT, Feng Y, Iura A, Giordano TJ, Kuick R, Kadikoy H,  et al. IRS1 regulation by Wnt/beta- catenin signaling and varied contribution of IRS1 to
the neoplastic phenotype. J Biol Chem 2010; 285:1928-1938.
19. Chan BT, Lee AV. Insulin receptor substrates (IRSs) and breast tumorigenesis. J  Mammary Gland Biol Neoplasia 2008; 13:415-422.
20.  Dearth RK, Cui X, Kim HJ, Kuiatse I, Lawrence NA, Zhang X, et al. Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. Mol Cell Biol 2006; 26:9302-9314.
21. Nagle JA, Ma Z, Byrne MA, White M F, Shaw LM. Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol Cell Biol 2004; 24:9726-9735.
22.  Zhang Q, Tang Q, Qin D, Yu L, Huang R, Lv G, et al. Role of microRNA 30a targeting insulin receptor substrate 2 in colorectal tumorigenesis. Mol Cell Biol 2015; 35:988-1000.
23. Meyer K, Albaugh B, Schoenike B, Roopra A. Type 1 insulin-like growth factor receptor/insulin receptor substrate 1 signaling confers pathogenic bctivity on breast tumor cells lacking REST,molecular and cellular biology. 2015; 35:2991-3004.
24. Zheng H, Zhang F, Lin X, Huang C, Zhang Y, Li Y, et al. MicroRNA-1225-5p inhibits proliferation and metastasis of gastric carcinoma through repressing insulin receptor substrate-1 and activation of beta-catenin signaling. Oncotarget 2016; 7: 4647-4663.