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Article: Rho-kinase 2 is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasion

TitleRho-kinase 2 is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasion
Authors
Issue Date2009
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
Hepatology, 2009, v. 49 n. 5, p. 1583-1594 How to Cite?
AbstractDeregulation of Rho family small guanosine triphosphatases has been implicated in human carcinogenesis. Rho-kinases are downstream effectors of Rho guanosine triphosphatases in the regulation of cytoskeletal reorganization and cell motility. However, their functions in human cancers remain elusive. In this study, we aimed to investigate the role of Rho-kinases in hepatocellular carcinoma (HCC) tumor progression and invasion. We first examined the expression of the two Rho-kinases (ROCK1 and ROCK2) in human HCC, and found that ROCK2 was frequently overexpressed in primary HCCs (22/41 [53.66%]). Clinico-pathological analysis revealed that overexpression of ROCK2 was significantly associated with the presence of tumor microsatellite formation (P = 0.005), suggesting that deregulation of ROCK2 may contribute to the intrahepatic metastasis of HCC. Consistently, we demonstrated that stable overexpression of ROCK2 significantly enhanced cell motility and invasiveness in HCC cells. Conversely, stable knockdown of ROCK2 by short hairpin RNA approach remarkably reduced HCC cell migration and invasion. Moreover, orthotopic liver xenograft models provided further support that stable knockdown of ROCK2 suppressed HCC invasion in vivo. Stable knockdown of ROCK2 in HCC cells significantly inhibited Golgi reorientation, myosin phosphatase phosphorylation, and formations of stress fibers, filopodia, and lamellipodia; these molecular and cellular events are crucial for cell motility and cancer invasion. Conclusion: Our results indicate that ROCK2 was overexpressed in human HCCs, and this overexpression was associated with a more aggressive biological behavior. Our findings also demonstrate that ROCK2 played a significant role in regulating cytoskeletal events and contributed to the invasion of HCC. Copyright © 2009 by the American Association for the Study of Liver Diseases.
Persistent Identifierhttp://hdl.handle.net/10722/60563
ISSN
2015 Impact Factor: 11.711
2015 SCImago Journal Rankings: 4.752
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 7436/04M
RGC Central Allocation GrantHKU 1/06C
Funding Information:

Supported by the Hong Kong Research Grants Council (HKU 7436/04M) and an RGC Central Allocation Grant (HKU 1/06C). I.O.L.N. is Loke Yew Professor in Pathology.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorWong, CCLen_HK
dc.contributor.authorWong, CMen_HK
dc.contributor.authorTung, EKKen_HK
dc.contributor.authorMan, Ken_HK
dc.contributor.authorNg, IOLen_HK
dc.date.accessioned2010-05-31T04:13:44Z-
dc.date.available2010-05-31T04:13:44Z-
dc.date.issued2009en_HK
dc.identifier.citationHepatology, 2009, v. 49 n. 5, p. 1583-1594en_HK
dc.identifier.issn0270-9139en_HK
dc.identifier.urihttp://hdl.handle.net/10722/60563-
dc.description.abstractDeregulation of Rho family small guanosine triphosphatases has been implicated in human carcinogenesis. Rho-kinases are downstream effectors of Rho guanosine triphosphatases in the regulation of cytoskeletal reorganization and cell motility. However, their functions in human cancers remain elusive. In this study, we aimed to investigate the role of Rho-kinases in hepatocellular carcinoma (HCC) tumor progression and invasion. We first examined the expression of the two Rho-kinases (ROCK1 and ROCK2) in human HCC, and found that ROCK2 was frequently overexpressed in primary HCCs (22/41 [53.66%]). Clinico-pathological analysis revealed that overexpression of ROCK2 was significantly associated with the presence of tumor microsatellite formation (P = 0.005), suggesting that deregulation of ROCK2 may contribute to the intrahepatic metastasis of HCC. Consistently, we demonstrated that stable overexpression of ROCK2 significantly enhanced cell motility and invasiveness in HCC cells. Conversely, stable knockdown of ROCK2 by short hairpin RNA approach remarkably reduced HCC cell migration and invasion. Moreover, orthotopic liver xenograft models provided further support that stable knockdown of ROCK2 suppressed HCC invasion in vivo. Stable knockdown of ROCK2 in HCC cells significantly inhibited Golgi reorientation, myosin phosphatase phosphorylation, and formations of stress fibers, filopodia, and lamellipodia; these molecular and cellular events are crucial for cell motility and cancer invasion. Conclusion: Our results indicate that ROCK2 was overexpressed in human HCCs, and this overexpression was associated with a more aggressive biological behavior. Our findings also demonstrate that ROCK2 played a significant role in regulating cytoskeletal events and contributed to the invasion of HCC. Copyright © 2009 by the American Association for the Study of Liver Diseases.en_HK
dc.languageengen_HK
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.en_HK
dc.subject.meshActins - metabolismen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshCarcinoma, Hepatocellular - enzymology - pathologyen_HK
dc.subject.meshCell Line, Tumoren_HK
dc.subject.meshCell Movementen_HK
dc.subject.meshGene Knockdown Techniquesen_HK
dc.subject.meshGolgi Apparatus - physiologyen_HK
dc.subject.meshHumansen_HK
dc.subject.meshLiver - pathologyen_HK
dc.subject.meshLiver Neoplasms - enzymology - pathologyen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMice, Inbred BALB Cen_HK
dc.subject.meshMice, Nudeen_HK
dc.subject.meshMyosin-Light-Chain Phosphatase - metabolismen_HK
dc.subject.meshNeoplasm Invasivenessen_HK
dc.subject.meshPhosphorylationen_HK
dc.subject.meshPseudopodia - metabolismen_HK
dc.subject.meshStress Fibers - metabolismen_HK
dc.subject.meshrho-Associated Kinases - metabolismen_HK
dc.titleRho-kinase 2 is frequently overexpressed in hepatocellular carcinoma and involved in tumor invasionen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0270-9139&volume=49 &issue=5&spage=1583&epage=1594&date=2009&atitle=Rho-kinase+2+is+frequently+overexpressed+in+hepatocellular+carcinoma+and+involved+in+tumor+invasion.en_HK
dc.identifier.emailWong, CCL: carmencl@pathology.hku.hken_HK
dc.identifier.emailWong, CM: jackwong@pathology.hku.hken_HK
dc.identifier.emailMan, K: kwanman@hkucc.hku.hken_HK
dc.identifier.emailNg, IOL: iolng@hkucc.hku.hken_HK
dc.identifier.authorityWong, CCL=rp01602en_HK
dc.identifier.authorityWong, CM=rp00231en_HK
dc.identifier.authorityMan, K=rp00417en_HK
dc.identifier.authorityNg, IOL=rp00335en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/hep.22836en_HK
dc.identifier.pmid19205033-
dc.identifier.scopuseid_2-s2.0-66149095045en_HK
dc.identifier.hkuros155430en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-66149095045&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume49en_HK
dc.identifier.issue5en_HK
dc.identifier.spage1583en_HK
dc.identifier.epage1594en_HK
dc.identifier.eissn1527-3350-
dc.identifier.isiWOS:000265668500021-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study-
dc.relation.projectFunctional characterization of DLC1 gene, a novel tumour suppressor gene frequently deleted in liver cancer-
dc.identifier.scopusauthoridWong, CCL=24823630000en_HK
dc.identifier.scopusauthoridWong, CM=16314668400en_HK
dc.identifier.scopusauthoridTung, EKK=7003519614en_HK
dc.identifier.scopusauthoridMan, K=7101754072en_HK
dc.identifier.scopusauthoridNg, IOL=7102753722en_HK

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