MicroRNA-101 regulates T-cell acute lymphoblastic leukemia progression and chemotherapeutic sensitivity by targeting Notch1

Qian,Lu; Zhang,Wanggang; Lei,Bo; He,Aili; Ye,Lianhong; Li,Xingzhou; Dong,Xin

doi:10.3892/or.2016.5117

MicroRNA-101 regulates T-cell acute lymphoblastic leukemia progression and chemotherapeutic sensitivity by targeting Notch1

Authors:
- Lu Qian
- Wanggang Zhang
- Bo Lei
- Aili He
- Lianhong Ye
- Xingzhou Li
- Xin Dong
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Affiliations: Department of Hematology, The Second Affiliated Hospital οf Xi'an Jiaotong University, Xi'an, Shaanxi 710005, P.R. China, Department of Gynaecology and Obstetrics, Xi'an No. 4 Hospital, Xi'an, Shaanxi 710004, P.R. China, Department of Surgery, Xi'an No. 4 Hospital, Xi'an, Shaanxi 710004, P.R. China, Department of Internal Medicine, Xi'an No. 4 Hospital, Xi'an, Shaanxi 710004, P.R. China
Published online on: September 21, 2016 https://doi.org/10.3892/or.2016.5117
Pages: 2511-2516
Copyright: © Qian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to investigate the role of microRNA (miR)-101 in acute lymphoblastic leukemia progression and chemoresistance. Furthermore, a novel target gene of miR-101 was identified. Here, we confirmed that miR-101 was significantly downregulated in the blood samples of patients with T-cell acute lymphoblastic leukemia (T-ALL) compared with the healthy controls, as determined by reverse transcription quantitative polymerase chain reaction (RTqPCR) analysis. The in vitro experiments demonstrated that miR-101 significantly repressed the proliferation and invasion, and induced potent apoptosis in Jurkat cells, as determined by CCK-8, flow cytometer and cell invasion assays. Luciferase assay confirmed that Notch1 was a target gene of miR-101, and western blotting showed that miR-101 suppressed the expression of Notch1 at the protein level. Moreover, functional restoration assays revealed that Notch1 mediates the effects of miR-101 on Jurkat cell proliferation, apoptosis and invasion. miR-101 enhanced the sensitivity of Jurkat cells to the chemotherapeutic agent adriamycin. Taken together, our results show for the first time that miR-101 acts as a tumor suppressor in T-cell acute lymphoblastic leukaemia and it could enhance chemotherapeutic sensitivity. Furthermore, Notch1 was identified to be a novel target of miR-101. This study indicates that miR-101 may represent a potential therapeutic target for T-cell acute lymphoblastic leukemia intervention.

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1	Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC, Behm FG, Pui CH, Downing JR, Gilliland DG, et al: Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell. 1:75–87. 2002. View Article : Google Scholar : PubMed/NCBI
2	Pui CH, Robison LL and Look AT: Acute lymphoblastic leukaemia. Lancet. 371:1030–1043. 2008. View Article : Google Scholar : PubMed/NCBI
3	Goldberg JM, Silverman LB, Levy DE, Dalton VK, Gelber RD, Lehmann L, Cohen HJ, Sallan SE and Asselin BL: Childhood T-cell acute lymphoblastic leukemia: The Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol. 21:3616–3622. 2003. View Article : Google Scholar : PubMed/NCBI
4	Oudot C, Auclerc MF, Levy V, Porcher R, Piguet C, Perel Y, Gandemer V, Debre M, Vermylen C, Pautard B, et al: Prognostic factors for leukemic induction failure in children with acute lymphoblastic leukemia and outcome after salvage therapy: The FRALLE 93 study. J Clin Oncol. 26:1496–1503. 2008. View Article : Google Scholar : PubMed/NCBI
5	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
6	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
7	Seca H, Almeida GM, Guimarães JE and Vasconcelos MH: miR signatures and the role of miRs in acute myeloid leukaemia. Eur J Cancer. 46:1520–1527. 2010. View Article : Google Scholar : PubMed/NCBI
8	Giza DE and Calin GA: microRNA and chronic lymphocytic leukemia. Adv Exp Med Biol. 889:23–40. 2015. View Article : Google Scholar : PubMed/NCBI
9	Yendamuri S and Calin GA: The role of microRNA in human leukemia: A review. Leukemia. 23:1257–1263. 2009. View Article : Google Scholar : PubMed/NCBI
10	Zhou X, Xia Y, Li L and Zhang G: MiR-101 inhibits cell growth and tumorigenesis of Helicobacter pylori related gastric cancer by repression of SOCS2. Cancer Biol Ther. 16:160–169. 2015. View Article : Google Scholar : PubMed/NCBI
11	Hao Y, Gu X, Zhao Y, Greene S, Sha W, Smoot DT, Califano J, Wu TC and Pang X: Enforced expression of miR-101 inhibits prostate cancer cell growth by modulating the COX-2 pathway in vivo. Cancer Prev Res (Phila). 4:1073–1083. 2011. View Article : Google Scholar
12	Sakurai T, Bilim VN, Ugolkov AV, Yuuki K, Tsukigi M, Motoyama T and Tomita Y: The enhancer of zeste homolog 2 (EZH2), a potential therapeutic target, is regulated by miR-101 in renal cancer cells. Biochem Biophys Res Commun. 422:607–614. 2012. View Article : Google Scholar : PubMed/NCBI
13	Luo C, Merz PR, Chen Y, Dickes E, Pscherer A, Schadendorf D and Eichmüller SB: MiR-101 inhibits melanoma cell invasion and proliferation by targeting MITF and EZH2. Cancer Lett. 341:240–247. 2013. View Article : Google Scholar : PubMed/NCBI
14	Robertus JL, Kluiver J, Weggemans C, Harms G, Reijmers RM, Swart Y, Kok K, Rosati S, Schuuring E, van Imhoff G, et al: MiRNA profiling in B non-Hodgkin lymphoma: A MYC-related miRNA profile characterizes Burkitt lymphoma. Br J Haematol. 149:896–899. 2010. View Article : Google Scholar : PubMed/NCBI
15	Cheng J, Guo S, Chen S, Mastriano SJ, Liu C, D'Alessio AC, Hysolli E, Guo Y, Yao H, Megyola CM, et al: An extensive network of TET2-targeting MicroRNAs regulates malignant hematopoiesis. Cell Rep. 5:471–481. 2013. View Article : Google Scholar : PubMed/NCBI
16	Papakonstantinou N, Ntoufa S, Chartomatsidou E, Papadopoulos G, Hatzigeorgiou A, Anagnostopoulos A, Chlichlia K, Ghia P, Muzio M, Belessi C, et al: Differential microRNA profiles and their functional implications in different immunogenetic subsets of chronic lymphocytic leukemia. Mol Med. 19:115–123. 2013. View Article : Google Scholar : PubMed/NCBI
17	Correia NC, Melão A, Póvoa V, Sarmento L, Gómez de Cedrón M, Malumbres M, Enguita FJ and Barata JT: microRNAs regulate TAL1 expression in T-cell acute lymphoblastic leukemia. Oncotarget. 7:8268–8281. 2016.PubMed/NCBI
18	Sethi N and Kang Y: Notch signalling in cancer progression and bone metastasis. Br J Cancer. 105:1805–1810. 2011. View Article : Google Scholar : PubMed/NCBI
19	Roy M, Pear WS and Aster JC: The multifaceted role of Notch in cancer. Curr Opin Genet Dev. 17:52–59. 2007. View Article : Google Scholar
20	Sahlgren C, Gustafsson MV, Jin S, Poellinger L and Lendahl U: Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA. 105:6392–6397. 2008. View Article : Google Scholar : PubMed/NCBI
21	Liu N, Zhang J and Ji C: The emerging roles of Notch signaling in leukemia and stem cells. Biomark Res. 1:232013. View Article : Google Scholar : PubMed/NCBI
22	Zou J, Li P, Lu F, Liu N, Dai J, Ye J, Qu X, Sun X, Ma D, Park J, et al: Notch1 is required for hypoxia-induced proliferation, invasion and chemoresistance of T-cell acute lymphoblastic leukemia cells. J Hematol Oncol. 6:32013. View Article : Google Scholar : PubMed/NCBI
23	Ninomiya S, Tyybäkinoja A, Borze I, Räty R, Saarinen-Pihkala UM, Usvasalo A, Elonen E and Knuutila S: Integrated analysis of gene copy number, copy neutral LOH, and microRNA profiles in adult acute lymphoblastic leukemia. Cytogenet Genome Res. 136:246–255. 2012. View Article : Google Scholar : PubMed/NCBI
24	Fallah P, Amirizadeh N, Poopak B, Toogeh G, Arefian E, Kohram F, Hosseini Rad SM, Kohram M, Teimori Naghadeh H and Soleimani M: Expression pattern of key microRNAs in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Int J Lab Hematol. 37:560–568. 2015. View Article : Google Scholar : PubMed/NCBI
25	Su H, Yang JR, Xu T, Huang J, Xu L, Yuan Y and Zhuang SM: MicroRNA-101, down-regulated in hepatocellular carcinoma, promotes apoptosis and suppresses tumorigenicity. Cancer Res. 69:1135–1142. 2009. View Article : Google Scholar : PubMed/NCBI
26	Liu XY, Liu ZJ, He H, Zhang C and Wang YL: MicroRNA-101-3p suppresses cell proliferation, invasion and enhances chemotherapeutic sensitivity in salivary gland adenoid cystic carcinoma by targeting Pim-1. Am J Cancer Res. 5:3015–3029. 2015.PubMed/NCBI
27	Li JT, Jia LT, Liu NN, Zhu XS, Liu QQ, Wang XL, Yu F, Liu YL, Yang AG and Gao CF: MiRNA-101 inhibits breast cancer growth and metastasis by targeting CX chemokine receptor 7. Oncotarget. 6:30818–30830. 2015.PubMed/NCBI
28	Zheng HB, Zheng XG and Liu BP: miRNA-101 inhibits ovarian cancer cells proliferation and invasion by down-regulating expression of SOCS-2. Int J Clin Exp Med. 8:20263–20270. 2015.
29	Capaccione KM and Pine SR: The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis. 34:1420–1430. 2013. View Article : Google Scholar : PubMed/NCBI
30	O'Neil J, Calvo J, McKenna K, Krishnamoorthy V, Aster JC, Bassing CH, Alt FW, Kelliher M and Look AT: Activating Notch1 mutations in mouse models of T-ALL. Blood. 107:781–785. 2006. View Article : Google Scholar
31	Chan SM, Weng AP, Tibshirani R, Aster JC and Utz PJ: Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood. 110:278–286. 2007. View Article : Google Scholar : PubMed/NCBI
32	Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E, Sulis ML, Barnes K, Sawai C, Homminga I, et al: Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med. 15:50–58. 2009. View Article : Google Scholar
33	Nefedova Y, Cheng P, Alsina M, Dalton WS and Gabrilovich DI: Involvement of Notch-1 signaling in bone marrow stromamediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood. 103:3503–3510. 2004. View Article : Google Scholar
34	Nefedova Y, Sullivan DM, Bolick SC, Dalton WS and Gabrilovich DI: Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood. 111:2220–2229. 2008. View Article : Google Scholar