Oncogenic miR-20a and miR-106a enhance the invasiveness of human glioma stem cells by directly targeting TIMP-2.
Emerging evidence has shown that cancer stem cells (CSCs) are the cellular determinants to promote cancer invasion and metastasis. However, the mechanism underlying CSC invasion remains unknown. MicroRNAs are evolutionally conserved small noncoding RNAs that are critical for the regulation of gene expression, and their expressions are often dysregulated in cancers. In the present study, we demonstrated that two functionally related microRNAs, miR-20a and -106a (miR-20a/106a), were capable of enhancing the invasiveness of CD133(+) glioma stem cells (GSCs) isolated from both glioblastoma cell line U87 and primary human glioma specimens. We found that the level of miR-20a/106a in GSCs was significantly higher than that in the committed CD133(-) glioma cells, and correlated with the invasive capability of GSCs. By bioinformatic analysis, we identified tissue inhibitor of metalloproteinases-2 (TIMP-2) as one of the miR-20a/106a-targeted genes. TIMP-2 level correlated inversely with miR-20/106 expression. Directly targeting by miR-20a/106a on 3'-untranslation region (3'-UTR) of TIMP-2 mRNA was confirmed by 3'-UTR dual-luciferase reporter assay. Knockdown of miR-20a/106a in GSCs increased endogenous TIMP-2 protein abundance, thereby inhibiting GSC invasion. We also found that Nordy, a synthetic lipoxygenase inhibitor, inhibited GSC invasiveness by elevating the expression of TIMP-2 via downregulation of miR-20a/106a. Our results indicate that miR-20a/106a has a key role in GSC invasion and may serve as targets for treatment of glioblastoma.
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Z
Z
Wang
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
B
B
Wang
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Y
Y
Shi
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
C
C
Xu
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
H L
HL
Xiao
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
L N
LN
Ma
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
S L
SL
Xu
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
L
L
Yang
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Q L
QL
Wang
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
W Q
WQ
Dang
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
W
W
Cui
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
S C
SC
Yu
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Y F
YF
Ping
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
Y H
YH
Cui
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
H F
HF
Kung
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
C
C
Qian
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
X
X
Zhang
Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
X W
XW
Bian
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000473:pathology*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009637:Masoprocol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells; D010455:Peptides / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000502:physiology*; D014183:Transplantation, Heterologous
D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; D016859:Lipoxygenase Inhibitors; C542541:MIRN106 microRNA, human; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D034741:RNA, Small Interfering; C510003:nordy; D019716:Tissue Inhibitor of Metalloproteinase-2; D009637:Masoprocol