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Article: Deleted in liver cancer 1 (DLC1) negatively regulates Rho/ROCK/MLC pathway in hepatocellular carcinoma

TitleDeleted in liver cancer 1 (DLC1) negatively regulates Rho/ROCK/MLC pathway in hepatocellular carcinoma
Authors
Issue Date2008
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
Plos One, 2008, v. 3 n. 7 How to Cite?
AbstractAims: Deleted in liver cancer 1 (DLC1), a member of RhoGTPase activating protein (GAP) family, is known to have suppressive activities in tumorigenicity and cancer metastasis. However, the underlying molecular mechanisms of how DLC1 suppresses cell motility have not been fully elucidated. Rho-kinase (ROCK) is an immediate down-stream effector of RhoA in mediating cellular cytoskeletal events and cell motility. In the present study, we aimed to investigate the effects of DLC1 on Rho/ROCK signaling pathway in hepatocellular carcinoma (HCC). Methodology/Principal Findings: We demonstrated that DLC1 negatively regulated ROCK-dependent actomyosin contractility. From immumofluorescence study, we found that ectopic expression of DLC1 abrogated Rho/ROCK-mediated cytoskeletal reorganization including formation of stress fibers and focal adhesions. It also downregulated cortical phosphorylation of myosin light chain 2 (MLC2). These inhibitory events by DLC1 were RhoGAP-dependent, as RhoGAP-deficient mutant of DLC1 (DLC1 K714E) abolished these inhibitory events. In addition, from western study, DLC1 inhibited ROCK-related myosin light chain phosphatase targeting unit 1 (MYPT1) phosphorylation at Threonine 853. By examining cell morphology under microscope, we found that ectopic expression of dominant-active ROCK released cells from DLC1-induced cytoskeletal collapse and cell shrinkage. Conclusion: Our data suggest that DLC1 negatively regulates Rho/ROCK/ MLC2. This implicates a ROCK-mediated pathway of DLC1 in suppressing metastasis of HCC cells and enriches our understanding in the molecular mechanisms involved in the progression of hepatocellular carcinoma. © 2008 Wong et al.
Persistent Identifierhttp://hdl.handle.net/10722/60559
ISSN
2015 Impact Factor: 3.057
2015 SCImago Journal Rankings: 1.395
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 7436/04M
RGC Collaborative Reseaarch FundHKU 1/06C
Michael and Betty Kadoorie Cancer Genetics Research Program 2004
Funding Information:

The study was funded by Hong Kong Research Grants Council (HKU 7436/04M), RGC Collaborative Reseaarch Fund (HKU 1/06C), Michael and Betty Kadoorie Cancer Genetics Research Program 2004. I.O.L. Ng is Loke Yew Professor in Pathology.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorWong, CCLen_HK
dc.contributor.authorWong, CMen_HK
dc.contributor.authorKo, FCFen_HK
dc.contributor.authorChan, LKen_HK
dc.contributor.authorChing, YPen_HK
dc.contributor.authorYam, JWPen_HK
dc.contributor.authorNg, IOIen_HK
dc.date.accessioned2010-05-31T04:13:39Z-
dc.date.available2010-05-31T04:13:39Z-
dc.date.issued2008en_HK
dc.identifier.citationPlos One, 2008, v. 3 n. 7en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/60559-
dc.description.abstractAims: Deleted in liver cancer 1 (DLC1), a member of RhoGTPase activating protein (GAP) family, is known to have suppressive activities in tumorigenicity and cancer metastasis. However, the underlying molecular mechanisms of how DLC1 suppresses cell motility have not been fully elucidated. Rho-kinase (ROCK) is an immediate down-stream effector of RhoA in mediating cellular cytoskeletal events and cell motility. In the present study, we aimed to investigate the effects of DLC1 on Rho/ROCK signaling pathway in hepatocellular carcinoma (HCC). Methodology/Principal Findings: We demonstrated that DLC1 negatively regulated ROCK-dependent actomyosin contractility. From immumofluorescence study, we found that ectopic expression of DLC1 abrogated Rho/ROCK-mediated cytoskeletal reorganization including formation of stress fibers and focal adhesions. It also downregulated cortical phosphorylation of myosin light chain 2 (MLC2). These inhibitory events by DLC1 were RhoGAP-dependent, as RhoGAP-deficient mutant of DLC1 (DLC1 K714E) abolished these inhibitory events. In addition, from western study, DLC1 inhibited ROCK-related myosin light chain phosphatase targeting unit 1 (MYPT1) phosphorylation at Threonine 853. By examining cell morphology under microscope, we found that ectopic expression of dominant-active ROCK released cells from DLC1-induced cytoskeletal collapse and cell shrinkage. Conclusion: Our data suggest that DLC1 negatively regulates Rho/ROCK/ MLC2. This implicates a ROCK-mediated pathway of DLC1 in suppressing metastasis of HCC cells and enriches our understanding in the molecular mechanisms involved in the progression of hepatocellular carcinoma. © 2008 Wong et al.en_HK
dc.languageengen_HK
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_HK
dc.relation.ispartofPLoS ONEen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshCarcinoma, Hepatocellular - metabolism-
dc.subject.meshCardiac Myosins - metabolism-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshLiver Neoplasms - metabolism-
dc.subject.meshMyosin Light Chains - metabolism-
dc.titleDeleted in liver cancer 1 (DLC1) negatively regulates Rho/ROCK/MLC pathway in hepatocellular carcinomaen_HK
dc.typeArticleen_HK
dc.identifier.emailWong, CCL:carmencl@pathology.hku.hken_HK
dc.identifier.emailWong, CM:jackwong@pathology.hku.hken_HK
dc.identifier.emailChing, YP:ypching@hku.hken_HK
dc.identifier.emailYam, JWP:judyyam@pathology.hku.hken_HK
dc.identifier.emailNg, IOI:iolng@hkucc.hku.hken_HK
dc.identifier.authorityWong, CCL=rp01602en_HK
dc.identifier.authorityWong, CM=rp00231en_HK
dc.identifier.authorityChing, YP=rp00469en_HK
dc.identifier.authorityYam, JWP=rp00468en_HK
dc.identifier.authorityNg, IOI=rp00335en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0002779en_HK
dc.identifier.pmid18648664-
dc.identifier.pmcidPMC2464714-
dc.identifier.scopuseid_2-s2.0-50649114599en_HK
dc.identifier.hkuros156766en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-50649114599&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume3en_HK
dc.identifier.issue7en_HK
dc.identifier.spagee2779-
dc.identifier.epagee2779-
dc.identifier.eissn1932-6203-
dc.identifier.isiWOS:000264302900049-
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.scopusauthoridKo, FCF=14630572500en_HK
dc.identifier.scopusauthoridChan, LK=24833005000en_HK
dc.identifier.scopusauthoridChing, YP=7005431277en_HK
dc.identifier.scopusauthoridYam, JWP=6603711123en_HK
dc.identifier.scopusauthoridNg, IOI=7102753722en_HK

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