title: MicroRNA-193a represses c-kit expression and functions as a methylation-silenced tumor suppressor in acute myeloid leukemia.
abstract: Aberrant activation of c-kit proto-oncogene contributes to abnormal cell proliferation by altering the tyrosine kinase signaling and constitutes a crucial impetus for leukemogenesis. Epigenetic silencing of tumor-suppressive microRNAs (miRNAs) is a key oncogenic mechanism for the activation of oncogenes in tumors. In this study, several miRNAs potentially binding to the 3'-untranslated region of human c-kit mRNA were screened by luciferase reporter assays. Among these miRNAs, miR-193a was embedded in a CpG island and epigenetically repressed by promoter hypermethylation in acute myeloid leukemia (AML) cell lines and primary AML blasts, but not in normal bone marrow cells. Importantly, miR-193a levels were inversely correlated with c-kit levels measured in 9 leukemia cell lines and 27 primary AML samples. Restoring miR-193a expression in AML cells harboring c-kit mutation and/or overexpression, either by synthetic miR-193a transfection or by DNA hypomethylating agent 5-azacytidine (5-aza) treatment, resulted in a significant reduction in c-kit expression at both RNA and protein levels and inhibition of cell growth. The growth-inhibitory activity of miR-193a was associated with apoptosis and granulocytic differentiation. Moreover, 5-aza-induced c-kit reduction could be partially blocked by miR-193a inhibitor, leading to a reversal of antiproliferative and proapoptotic effects of 5-aza. These data reveal a critical role for methylation-repressed miR-193a in myeloid leukemogenesis and the therapeutic promise of upregulating miR-193a expression for c-kit-positive AML.
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: X-N
authors.initials: XN
authors.lastname: Gao
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.forename: Y-H
authors.initials: YH
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Gao
authors.forename: X-R
authors.initials: XR
authors.lastname: Wang
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: H-Y
authors.initials: HY
authors.lastname: Kang
authors.forename: G-T
authors.initials: GT
authors.lastname: Yan
authors.forename: L-L
authors.initials: LL
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Yu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D001374:Azacitidine / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit; D001374:Azacitidine