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Article: Loss of phosphatase and tensin homolog enhances cell invasion and migration through aKT/Sp-1 transcription factor/matrix metalloproteinase 2 activation in hepatocellular carcinoma and has clinicopathologic significance

TitleLoss of phosphatase and tensin homolog enhances cell invasion and migration through aKT/Sp-1 transcription factor/matrix metalloproteinase 2 activation in hepatocellular carcinoma and has clinicopathologic significance
Authors
Issue Date2011
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
Hepatology, 2011, v. 53 n. 5, p. 1558-1569 How to Cite?
AbstractPhosphatase and tensin homolog (PTEN) is frequently inactivated in cancers and is associated with advanced stages of cancers or metastasis. However, the molecular mechanism of PTEN in hepatocellular carcinoma (HCC) metastasis is unclear. In this study, we found frequent (47.5%, n = 40) protein underexpression of PTEN in human HCCs compared with their corresponding nontumorous livers. Significantly, PTEN underexpression was associated with larger tumor size (P = 0.021), tumor microsatellite formation (P = 0.027), and shorter overall survival of patients (P = 0.035). Using different cell models, we observed that PTEN-knockdown HCC cells and PTEN-knockout mouse embryonic fibroblasts (MEFs) had enhanced cell migratory and invasive abilities. In addition to activation of AKT, there was up-regulation of the Sp1 transcription factor (SP1) and matrix metalloproteinase 2 (MMP2), as well as MMP2 activation in PTEN-knockdown HCC cells and PTEN -/- MEFs. With dual luciferase reporter assay, exogenous expression of SP1 in HCC cells led to enhanced MMP2 promoter activity by up to 74%, whereas deletion of the putative SP1 binding site on the MMP2 promoter led to reduced promoter activity by up to 65%. Using chromatin immunoprecipitation assay, we documented increased binding of SP1 to the MMP2 promoter in PTEN-knockdown HCC cells. Overexpression of SP1 and MMP2 was significantly but negatively associated with PTEN underexpression in human HCCs. Conclusion: Our results show that PTEN was underexpressed in HCCs, and this underexpression was associated with more aggressive biological behavior and poorer patient survival. We have provided the first evidence that MMP2 up-regulation upon PTEN loss is SP1-dependent. Our findings indicate that PTEN plays a significant role in down-regulating HCC cell invasion via the AKT/SP1/MMP2 pathway. © 2011 American Association for the Study of Liver Diseases.
Persistent Identifierhttp://hdl.handle.net/10722/137619
ISSN
2023 Impact Factor: 12.9
2023 SCImago Journal Rankings: 5.011
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 1/06C
HKU 7/CRF/09
Funding Information:

Supported by a Hong Kong Research Grants Council Collaborative Research Fund (HKU 1/06C and HKU 7/CRF/09). I. O.-L. Ng is Loke Yew Professor in Pathology.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorSze, KMFen_HK
dc.contributor.authorWong, KLTen_HK
dc.contributor.authorChu, GKYen_HK
dc.contributor.authorLee, JMFen_HK
dc.contributor.authorYau, TOen_HK
dc.contributor.authorNg, IOLen_HK
dc.date.accessioned2011-08-26T14:29:24Z-
dc.date.available2011-08-26T14:29:24Z-
dc.date.issued2011en_HK
dc.identifier.citationHepatology, 2011, v. 53 n. 5, p. 1558-1569en_HK
dc.identifier.issn0270-9139en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137619-
dc.description.abstractPhosphatase and tensin homolog (PTEN) is frequently inactivated in cancers and is associated with advanced stages of cancers or metastasis. However, the molecular mechanism of PTEN in hepatocellular carcinoma (HCC) metastasis is unclear. In this study, we found frequent (47.5%, n = 40) protein underexpression of PTEN in human HCCs compared with their corresponding nontumorous livers. Significantly, PTEN underexpression was associated with larger tumor size (P = 0.021), tumor microsatellite formation (P = 0.027), and shorter overall survival of patients (P = 0.035). Using different cell models, we observed that PTEN-knockdown HCC cells and PTEN-knockout mouse embryonic fibroblasts (MEFs) had enhanced cell migratory and invasive abilities. In addition to activation of AKT, there was up-regulation of the Sp1 transcription factor (SP1) and matrix metalloproteinase 2 (MMP2), as well as MMP2 activation in PTEN-knockdown HCC cells and PTEN -/- MEFs. With dual luciferase reporter assay, exogenous expression of SP1 in HCC cells led to enhanced MMP2 promoter activity by up to 74%, whereas deletion of the putative SP1 binding site on the MMP2 promoter led to reduced promoter activity by up to 65%. Using chromatin immunoprecipitation assay, we documented increased binding of SP1 to the MMP2 promoter in PTEN-knockdown HCC cells. Overexpression of SP1 and MMP2 was significantly but negatively associated with PTEN underexpression in human HCCs. Conclusion: Our results show that PTEN was underexpressed in HCCs, and this underexpression was associated with more aggressive biological behavior and poorer patient survival. We have provided the first evidence that MMP2 up-regulation upon PTEN loss is SP1-dependent. Our findings indicate that PTEN plays a significant role in down-regulating HCC cell invasion via the AKT/SP1/MMP2 pathway. © 2011 American Association for the Study of Liver Diseases.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.subject.meshAdulten_HK
dc.subject.meshAgeden_HK
dc.subject.meshCarcinoma, Hepatocellular - metabolism - pathologyen_HK
dc.subject.meshCell Movementen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshHumansen_HK
dc.subject.meshLiver Neoplasms - metabolism - pathologyen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMatrix Metalloproteinase 2en_HK
dc.subject.meshMiddle Ageden_HK
dc.subject.meshNeoplasm Invasivenessen_HK
dc.subject.meshPTEN Phosphohydrolase - physiologyen_HK
dc.subject.meshProto-Oncogene Proteins c-akt - physiologyen_HK
dc.subject.meshSp1 Transcription Factor - physiologyen_HK
dc.subject.meshTumor Cells, Cultureden_HK
dc.titleLoss of phosphatase and tensin homolog enhances cell invasion and migration through aKT/Sp-1 transcription factor/matrix metalloproteinase 2 activation in hepatocellular carcinoma and has clinicopathologic significanceen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1527-3350&volume=53&issue=5&spage=1558&epage=1569&date=2011&atitle=Loss+of+phosphatase+and+tensin+homolog+enhances+cell+invasion+and+migration+through+AKT/Sp-1+transcription+factor/matrix+metalloproteinase+2+activation+in+hepatocellular+carcinoma+and+has+clinicopathologic+significanceen_US
dc.identifier.emailOiLin Ng, I:iolng@hkucc.hku.hken_HK
dc.identifier.authorityOiLin Ng, I=rp00335en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1002/hep.24232en_HK
dc.identifier.pmid21520171-
dc.identifier.scopuseid_2-s2.0-79955110863en_HK
dc.identifier.hkuros189592en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79955110863&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume53en_HK
dc.identifier.issue5en_HK
dc.identifier.spage1558en_HK
dc.identifier.epage1569en_HK
dc.identifier.eissn1527-3350-
dc.identifier.isiWOS:000289956100017-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectMolecular Pathology of Liver Cancer - a Multidisciplinary Study-
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study-
dc.identifier.issnl0270-9139-

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