miR-137 and miR-197 Induce Apoptosis and Suppress Tumorigenicity by Targeting MCL-1 in Multiple Myeloma.
OBJECTIVE
Deregulation of miRNA has been implicated in the pathogenesis of multiple myeloma. We identified miR-137 and miR-197, mapped to the chromosome 1p (12)-(21) deletion region, and examined their antimyeloma activity as tumor suppressors.


METHODS
The expression of miR-137/197 was examined in multiple myeloma and normal plasma cells by qRT-PCR. Functional effect of miR-137/197 was analyzed by cell viability, apoptosis, clonogenic, and migration assays. Antimyeloma activity of miR-137/197 was further evaluated in vivo by lentiviral-based or lipid-based delivery in a mouse xenograft model of multiple myeloma.


RESULTS
miR-137/197 expression was significantly lower in multiple myeloma cell lines and multiple myeloma patient samples compared with normal plasma cells. Transfection of miR-137/197 resulted in reduction of MCL-1 protein expression, as well as alteration of apoptosis-related genes, and induction of apoptosis, inhibition of viability, colony formation, and migration in multiple myeloma cells. MCL-1 was further validated as a direct target of miR-137/197. Conversely, overexpression of MCL-1 partially reverted the effect of miR-137/197. Importantly, in vivo lentiviral-mediated or intratumor delivery of miR-137/197 induced regression of tumors in murine xenograft models of multiple myeloma.


CONCLUSIONS
Our study reveals a novel role of miR-137/197 as tumor suppressors in mediating apoptosis in multiple myeloma cells by targeting MCL-1. Our findings provide a proof-of-principle that lentivirus-based or formulated synthetic miR-137/197 exerts therapeutic activity in preclinical models, and support a framework for development of miR-137/197-based treatment strategies in patients with multiple myeloma.
Division of Molecular and Cellular Biology, Toronto General Research Institute, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Yijun
Y
Yang
Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
Fei
F
Li
Division of Molecular and Cellular Biology, Toronto General Research Institute, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Manujendra N
MN
Saha
Division of Molecular and Cellular Biology, Toronto General Research Institute, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Jahangir
J
Abdi
Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. Hong.Chang@uhn.on.ca qiulg@ihcams.ac.cn.
Lugui
L
Qiu
Division of Molecular and Cellular Biology, Toronto General Research Institute, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Laboratory Hematology and Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada. Hong.Chang@uhn.on.ca qiulg@ihcams.ac.cn.
Hong
H
Chang
D020413:3' Untranslated Regions; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D015316:Genetic Therapy; D057809:HEK293 Cells; D006801:Humans; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D034622:RNA Interference
D020413:3' Untranslated Regions; C579095:MCL1 protein, human; C545567:MIRN137 microRNA, human; C546085:MIRN197 microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D049410:Luciferases, Renilla; D049409:Luciferases, Firefly