miR-656 inhibits glioma tumorigenesis through repression of BMPR1A.
Bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-β family, plays critical roles in cell differentiation, modeling and regeneration processes in several tissues. BMP-2 is also closely associated with various malignant tumors. microRNAs negatively and posttranscriptionally regulate gene expression and function as oncogenes or tumor suppressors. Herein, we report that miR-656 expression was significantly downregulated in glioma cell lines and tissues. We identified and confirmed that BMP receptor, type 1A (BMPR1A) is a direct target of miR-656. The expression of BMPR1A was negatively correlated with that of miR-656 in human glioma tissues. We further demonstrated that miR-656 suppressed glioma cell proliferation, neurosphere formation, migration and invasion with or without exogenous BMP-2. Engineered knockdown of BMPR1A diminished the antiproliferation effect of miR-656 in vitro. Moreover, the canonical BMP/Smad and non-canonical BMP/mitogen-activated protein kinase (MAPK) pathways were inhibited by miR-656 overexpression. Several cancer-related signaling molecules, including cyclin B, cyclin D1, matrix metalloproteinase-9, p21 and p27, were also involved in miR-656 function in glioma cells. The tumor-suppressing function of miR-656 was validated using an in vivo intracranial xenograft mouse model. Notably, ectopic expression of miR-656 markedly reduced tumor size and prolonged the survival of mice treated with or without BMP-2. These results elucidate the function of miR-656 in glioma progression and suggest a promising application for glioma treatment.
Mian
M
Guo
Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
Zhenfeng
Z
Jiang
Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
Xiaoming
X
Zhang
Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China, Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
Dunyue
D
Lu
Dental School, University of California, Los Angeles, Los Angeles, CA 90095, USA and.
Albert Duy
AD
Ha
Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
Jiahang
J
Sun
Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
Wenzhong
W
Du
Department of Neurosurgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
Zhichao
Z
Wu
Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China.
Li
L
Hu
Dental School, University of California, Los Angeles, Los Angeles, CA 90095, USA and.
Kevork
K
Khadarian
Dental School, University of California, Los Angeles, Los Angeles, CA 90095, USA and linzhiguo@hotmail.com shenj02@gmail.com.
Jia
J
Shen
Department of Neurosurgery, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, China, linzhiguo@hotmail.com.
Zhiguo
Z
Lin
D000818:Animals; D015153:Blotting, Western; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014945:Wound Healing; D023041:Xenograft Model Antitumor Assays
D035683:MicroRNAs; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I