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Article: Brain-derived neurotrophic factor promotes tumorigenesis via induction of neovascularization: Implication in hepatocellular carcinoma

TitleBrain-derived neurotrophic factor promotes tumorigenesis via induction of neovascularization: Implication in hepatocellular carcinoma
Authors
KeywordsBrain derived neurotrophic factor
Angiogenesis
Animal cell
Cell invasion
Cell migration
Issue Date2011
PublisherAmerican Association for Cancer Research.
Citation
Clinical Cancer Research, 2011, v. 17 n. 10, p. 3123-3133 How to Cite?
Abstract
Purpose: Brain-derived neurotrophic factor (BDNF) has emerged as a novel angiogenic factor, and yet its impact on tumorigenesis is unclear. This study aimed at investigating the roles of BDNF in angiogenesis and tumor development. Experimental Design: BDNF was overexpressed in a mouse endothelial cell (EC) line by stable transfection, and angiogenic properties of the transfectants were assessed. Microarray analysis was employed to explore the molecular pathways. The impact of modulating BDNF levels in two mouse EC lines on tumorigenic potential of a transformed mouse liver cell line was evaluated by an in vivo cotransplantation model. BDNF and tropomyosin receptor kinase B (TrkB) protein levels were determined in 50 pairs of human hepatocellular carcinoma (HCC) tissues by Western blotting and immunohistochemistry. Survival analysis was carried out to determine their clinical significance. Results: Overexpression of BDNF could promote EC proliferation, migration, invasion, and survival. Microarray and molecular studies showed that RhoA, caspase-9, caspase-3, growth arrest specific 6, and VEGF could mediate BDNF/TrkB-induced angiogenesis. The cotransplantation experiment showed that high BDNF-expressing ECs could facilitate tumor angiogenesis and growth, whereas knockdown of BDNF by short hairpin RNAs impaired such effects. Furthermore, examination on human HCC tissues revealed upregulation of BDNF and TrkB protein levels in 46.0% and 33.3% of the cases studied, respectively. Immunohistochemistry disclosed strong BDNF reactivity in both tumor and endothelial cells. High TrkB expression was associated with shorter overall survival. Conclusions: BDNF/TrkB system was crucial for tumor angiogenesis and growth, which may represent a potential target for antiangiogenic therapy in HCC. ©2011 AACR.
Persistent Identifierhttp://hdl.handle.net/10722/135540
ISSN
2013 Impact Factor: 8.193
2013 SCImago Journal Rankings: 5.150
ISI Accession Number ID
Funding AgencyGrant Number
University of Hong Kong
Research Grant Council Hong KongHKU5/CRF/08
Funding Information:

This study was supported by Small Project Funding of the University of Hong Kong and by the Collaborative Research Fund (HKU5/CRF/08) of the Research Grant Council Hong Kong.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorLam, CTen_HK
dc.contributor.authorYang, ZFen_HK
dc.contributor.authorLau, CKen_HK
dc.contributor.authorTam, KHen_HK
dc.contributor.authorFan, STen_HK
dc.contributor.authorPoon, RTPen_HK
dc.date.accessioned2011-07-27T01:36:44Z-
dc.date.available2011-07-27T01:36:44Z-
dc.date.issued2011en_HK
dc.identifier.citationClinical Cancer Research, 2011, v. 17 n. 10, p. 3123-3133en_HK
dc.identifier.issn1078-0432en_HK
dc.identifier.urihttp://hdl.handle.net/10722/135540-
dc.description.abstractPurpose: Brain-derived neurotrophic factor (BDNF) has emerged as a novel angiogenic factor, and yet its impact on tumorigenesis is unclear. This study aimed at investigating the roles of BDNF in angiogenesis and tumor development. Experimental Design: BDNF was overexpressed in a mouse endothelial cell (EC) line by stable transfection, and angiogenic properties of the transfectants were assessed. Microarray analysis was employed to explore the molecular pathways. The impact of modulating BDNF levels in two mouse EC lines on tumorigenic potential of a transformed mouse liver cell line was evaluated by an in vivo cotransplantation model. BDNF and tropomyosin receptor kinase B (TrkB) protein levels were determined in 50 pairs of human hepatocellular carcinoma (HCC) tissues by Western blotting and immunohistochemistry. Survival analysis was carried out to determine their clinical significance. Results: Overexpression of BDNF could promote EC proliferation, migration, invasion, and survival. Microarray and molecular studies showed that RhoA, caspase-9, caspase-3, growth arrest specific 6, and VEGF could mediate BDNF/TrkB-induced angiogenesis. The cotransplantation experiment showed that high BDNF-expressing ECs could facilitate tumor angiogenesis and growth, whereas knockdown of BDNF by short hairpin RNAs impaired such effects. Furthermore, examination on human HCC tissues revealed upregulation of BDNF and TrkB protein levels in 46.0% and 33.3% of the cases studied, respectively. Immunohistochemistry disclosed strong BDNF reactivity in both tumor and endothelial cells. High TrkB expression was associated with shorter overall survival. Conclusions: BDNF/TrkB system was crucial for tumor angiogenesis and growth, which may represent a potential target for antiangiogenic therapy in HCC. ©2011 AACR.en_HK
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research.-
dc.relation.ispartofClinical Cancer Researchen_HK
dc.subjectBrain derived neurotrophic factor-
dc.subjectAngiogenesis-
dc.subjectAnimal cell-
dc.subjectCell invasion-
dc.subjectCell migration-
dc.titleBrain-derived neurotrophic factor promotes tumorigenesis via induction of neovascularization: Implication in hepatocellular carcinomaen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1078-0432&volume=17&issue=10&spage=3123&epage=3133&date=2011&atitle=Brain-derived+neurotrophic+factor+promotes+tumorigenesis+via+induction+of+neovascularization:+implication+in+hepatocellular+carcinoma-
dc.identifier.emailFan, ST: stfan@hku.hken_HK
dc.identifier.emailPoon, RTP: poontp@hkucc.hku.hken_HK
dc.identifier.authorityFan, ST=rp00355en_HK
dc.identifier.authorityPoon, RTP=rp00446en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-10-2802en_HK
dc.identifier.pmid21421859en_HK
dc.identifier.scopuseid_2-s2.0-79955990588en_HK
dc.identifier.hkuros187636en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79955990588&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume17en_HK
dc.identifier.issue10en_HK
dc.identifier.spage3123en_HK
dc.identifier.epage3133en_HK
dc.identifier.isiWOS:000290610000008-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury-
dc.identifier.scopusauthoridLam, CT=7402989860en_HK
dc.identifier.scopusauthoridYang, ZF=39863860200en_HK
dc.identifier.scopusauthoridLau, CK=7401968442en_HK
dc.identifier.scopusauthoridTam, KH=7201692833en_HK
dc.identifier.scopusauthoridFan, ST=7402678224en_HK
dc.identifier.scopusauthoridPoon, RTP=7103097223en_HK

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