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Article: MicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression

TitleMicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression
Authors
Issue Date2011
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
Hepatology, 2011, v. 54 n. 5, p. 1729-1740 How to Cite?
AbstractHepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent intrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. We previously found that microRNA-29b (miR-29b) down-regulation was significantly associated with poor recurrence-free survival of HCC patients. Therefore, the role of miR-29b in tumor angiogenesis, invasion, and metastasis was further investigated in this study using in vitro capillary tube formation and transwell assays, in vivo subcutaneous and orthotopic xenograft mouse models, and Matrigel plug assay, and human HCC samples. Both gain- and loss-of-function studies showed that miR-29b dramatically suppressed the ability of HCC cells to promote capillary tube formation of endothelial cells and to invade extracellular matrix gel in vitro. Using mouse models, we revealed that tumors derived from miR-29b-expressed HCC cells displayed significant reduction in microvessel density and in intrahepatic metastatic capacity compared with those from the control group. Subsequent investigations revealed that matrix metalloproteinase-2 (MMP-2) was a direct target of miR-29b. The blocking of MMP-2 by neutralizing antibody or RNA interference phenocopied the antiangiogenesis and antiinvasion effects of miR-29b, whereas introduction of MMP-2 antagonized the function of miR-29b. We further disclosed that miR-29b exerted its antiangiogenesis function, at least partly, by suppressing MMP-2 expression in tumor cells and, in turn, impairing vascular endothelial growth factor receptor 2-signaling in endothelial cells. Consistently, in human HCC tissues and mouse xenograft tumors miR-29b level was inversely correlated with MMP-2 expression, as well as tumor angiogenesis, venous invasion, and metastasis. CONCLUSION: miR-29b deregulation contributes to angiogenesis, invasion, and metastasis of HCC. Restoration of miR-29b represents a promising new strategy in anti-HCC therapy.
Persistent Identifierhttp://hdl.handle.net/10722/143747
ISSN
2015 Impact Factor: 11.711
2015 SCImago Journal Rankings: 4.752
ISI Accession Number ID
Funding AgencyGrant Number
Ministry of Science and Technology of China2010CB912803
2011CB811305
National Natural Science Foundation of China30925036
30700993
Ministry of Health of China2008ZX10002-019
Natural Science Foundation of Guangdong Province8451027501001496
Funding Information:

Supported by grants from Ministry of Science and Technology of China (2010CB912803, 2011CB811305), National Natural Science Foundation of China (30925036, 30700993), Ministry of Health of China (2008ZX10002-019), Natural Science Foundation of Guangdong Province (8451027501001496).

References

 

DC FieldValueLanguage
dc.contributor.authorFang, JHen_HK
dc.contributor.authorZhou, HCen_HK
dc.contributor.authorZeng, Cen_HK
dc.contributor.authorYang, Jen_HK
dc.contributor.authorLiu, Yen_HK
dc.contributor.authorHuang, Xen_HK
dc.contributor.authorZhang, JPen_HK
dc.contributor.authorGuan, XYen_HK
dc.contributor.authorZhuang, SMen_HK
dc.date.accessioned2011-12-21T08:48:24Z-
dc.date.available2011-12-21T08:48:24Z-
dc.date.issued2011en_HK
dc.identifier.citationHepatology, 2011, v. 54 n. 5, p. 1729-1740en_HK
dc.identifier.issn0270-9139en_HK
dc.identifier.urihttp://hdl.handle.net/10722/143747-
dc.description.abstractHepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent intrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. We previously found that microRNA-29b (miR-29b) down-regulation was significantly associated with poor recurrence-free survival of HCC patients. Therefore, the role of miR-29b in tumor angiogenesis, invasion, and metastasis was further investigated in this study using in vitro capillary tube formation and transwell assays, in vivo subcutaneous and orthotopic xenograft mouse models, and Matrigel plug assay, and human HCC samples. Both gain- and loss-of-function studies showed that miR-29b dramatically suppressed the ability of HCC cells to promote capillary tube formation of endothelial cells and to invade extracellular matrix gel in vitro. Using mouse models, we revealed that tumors derived from miR-29b-expressed HCC cells displayed significant reduction in microvessel density and in intrahepatic metastatic capacity compared with those from the control group. Subsequent investigations revealed that matrix metalloproteinase-2 (MMP-2) was a direct target of miR-29b. The blocking of MMP-2 by neutralizing antibody or RNA interference phenocopied the antiangiogenesis and antiinvasion effects of miR-29b, whereas introduction of MMP-2 antagonized the function of miR-29b. We further disclosed that miR-29b exerted its antiangiogenesis function, at least partly, by suppressing MMP-2 expression in tumor cells and, in turn, impairing vascular endothelial growth factor receptor 2-signaling in endothelial cells. Consistently, in human HCC tissues and mouse xenograft tumors miR-29b level was inversely correlated with MMP-2 expression, as well as tumor angiogenesis, venous invasion, and metastasis. CONCLUSION: miR-29b deregulation contributes to angiogenesis, invasion, and metastasis of HCC. Restoration of miR-29b represents a promising new strategy in anti-HCC therapy.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/en_HK
dc.relation.ispartofHepatologyen_HK
dc.rightsHepatology. Copyright © John Wiley & Sons, Inc.-
dc.subject.meshCapillaries - physiologyen_HK
dc.subject.meshCarcinoma, Hepatocellular - genetics - metabolism - secondaryen_HK
dc.subject.meshKidney Neoplasms - genetics - metabolism - pathologyen_HK
dc.subject.meshMicroRNAs - genetics - metabolismen_HK
dc.subject.meshNeovascularization, Pathologic - genetics - metabolism - pathologyen_HK
dc.titleMicroRNA-29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expressionen_HK
dc.typeArticleen_HK
dc.identifier.emailGuan, XY: xyguan@hkucc.hku.hken_HK
dc.identifier.emailZhuang, SM: zhuangshimei@163.com, LSSZSM@mail.sysu.edu.cn-
dc.identifier.authorityGuan, XY=rp00454en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/hep.24577en_HK
dc.identifier.pmid21793034-
dc.identifier.scopuseid_2-s2.0-80055047968en_HK
dc.identifier.hkuros198005en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80055047968&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume54en_HK
dc.identifier.issue5en_HK
dc.identifier.spage1729en_HK
dc.identifier.epage1740en_HK
dc.identifier.isiWOS:000296443100025-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridZhuang, SM=7102783035en_HK
dc.identifier.scopusauthoridGuan, XY=7201463221en_HK
dc.identifier.scopusauthoridZhang, JP=54399439700en_HK
dc.identifier.scopusauthoridHuang, X=35778292600en_HK
dc.identifier.scopusauthoridLiu, Y=54398916800en_HK
dc.identifier.scopusauthoridYang, J=16680461400en_HK
dc.identifier.scopusauthoridZeng, C=34877945900en_HK
dc.identifier.scopusauthoridZhou, HC=54399501800en_HK
dc.identifier.scopusauthoridFang, JH=54398485100en_HK

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