title: MicroRNA-494 Activation Suppresses Bone Marrow Stromal Cell-Mediated Drug Resistance in Acute Myeloid Leukemia Cells.
abstract: Acute myeloid leukemia (AML) is not sensitive to chemotherapy partially because of the protection of AML cells by mesenchymal stromal cells (MSCs). Our previous studies found that MSCs protected AML cells from apoptosis through the c-Myc-dependent pathway. However, the mechanism by which MSCs regulate c-Myc in AML cells is still unknown. To elucidate the mechanism, we performed microRNA array analysis of AML cell lines and validated by TaqMan realtime PCR. The results showed that the expression of microRNA-494 (miR-494) in AML cells after coculture with MSCs was downregulated. Reporter gene analysis confirmed miR-494 as one of the regulators of c-Myc. In the coculture system, activation of miR-494 in AML cells suppressed proliferation and induced apoptosis of AML cells in vitro. After addition of mitoxantrone to the coculture system, the proliferation of AML cells with miR-494 activation was suppressed more than that of control cells. After subcutaneous injection of AML cell lines in combination with MSC, tumor growth was suppressed in mice injected with miR-494-overexpressing AML cells. The rate of tumor formation was even lower after mitoxantrone treatment in the miR-494 overexpressing group. Moreover, miR-494 activation resulted in a decrease of leukemic cell counts in peripheral blood (PB) and bone marrow, and prolonged survival in mice injected with miR-494-overexpressing AML cellls and MSCs compared to the control mice. Our results indicate that miR-494 suppresses drug resistance in AML cells by downregulating c-Myc through interaction with MSCs and that miR-494 therefore is a potential therapeutic target. J. Cell. Physiol. 232: 1387-1395, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Hematology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, People's Republic of China.
authors.forename: Guoguang
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Department of Hematology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
authors.forename: Hongqing
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: Department of Hematology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
authors.forename: Xubin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hematology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
authors.forename: Dongzhi
authors.initials: D
authors.lastname: Hu
authors.affiliation: Department of Hematology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Hematology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
authors.forename: Tengteng
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mingjian James
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Hematology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
authors.forename: Yizhuo
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D063646:Carcinogenesis / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048430:Cell Shape; D018920:Coculture Techniques; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; C547168:MIRN494 microRNA, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc