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Article: HAI-2 is epigenetically downregulated in human hepatocellular carcinoma, and its Kunitz domain type 1 is critical for anti-invasive functions

TitleHAI-2 is epigenetically downregulated in human hepatocellular carcinoma, and its Kunitz domain type 1 is critical for anti-invasive functions
Authors
KeywordsEpigenetics
HAI-2
HCC
Kunitz domain
Serine protease inhibitor
Issue Date2009
PublisherJohn Wiley & Sons, Inc.. The Journal's web site is located at http://www3.interscience.wiley.com/journal/29331/home
Citation
International Journal Of Cancer, 2009, v. 124 n. 8, p. 1811-1819 How to Cite?
AbstractPharmacological demethylation-based gene expression profile analysis is a useful tool to identify epigenetically silenced tumour suppressor genes. HGF activator inhibitor 2 (HAI-2), a serine protease inhibitor, has been identified as one of the candidate tumour suppressor genes in human hepatocellular carcinoma (HCC) with this technique. In this study, we aimed to characterise the epigenetic status and tumour suppressive function of HAI-2 in HCC. We validated that HAI-2 expression was either absent or low in most of the HCC cell lines tested, and 5-Aza-2′-deoxycytidine treatment significantly restored its expression in 9 (75%) of these 12 cell lines. HAI-2 was found to be frequently underexpressed in human HCCs (p < 0.001). With bisulphite DNA sequencing and methylation-specific PCR, we found that the promoter of the HAI-2 gene was frequently hypermethylated in both HCC cell lines and human HCCs. Ectopic expression of HAI-2 significantly inhibited cell migration and invasiveness of HCC cells in vitro and suppressed tumourigenicity in vivo. In addition, we also provided the first evidence that HAI-2 mediated its tumour suppressor function via the Kunitz domain 1 (KD-1), as KD-1 but not KD-2 inactivating mutant abolished its anti-tumour invasiveness in vitro. Our findings suggest that HAI-2 is a candidate tumour suppressor gene that is frequently hypermethylated and underexpressed in human HCCs, and the KD-1 domain of HAI-2 is the key region responsible for its anti-invasive function. © 2008 Wiley-Liss, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/58190
ISSN
2015 Impact Factor: 5.531
2015 SCImago Journal Rankings: 2.657
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorTung, EKKen_HK
dc.contributor.authorWong, CMen_HK
dc.contributor.authorYau, TOen_HK
dc.contributor.authorLee, JMFen_HK
dc.contributor.authorChing, YPen_HK
dc.contributor.authorNg, IOLen_HK
dc.date.accessioned2010-05-31T03:25:31Z-
dc.date.available2010-05-31T03:25:31Z-
dc.date.issued2009en_HK
dc.identifier.citationInternational Journal Of Cancer, 2009, v. 124 n. 8, p. 1811-1819en_HK
dc.identifier.issn0020-7136en_HK
dc.identifier.urihttp://hdl.handle.net/10722/58190-
dc.description.abstractPharmacological demethylation-based gene expression profile analysis is a useful tool to identify epigenetically silenced tumour suppressor genes. HGF activator inhibitor 2 (HAI-2), a serine protease inhibitor, has been identified as one of the candidate tumour suppressor genes in human hepatocellular carcinoma (HCC) with this technique. In this study, we aimed to characterise the epigenetic status and tumour suppressive function of HAI-2 in HCC. We validated that HAI-2 expression was either absent or low in most of the HCC cell lines tested, and 5-Aza-2′-deoxycytidine treatment significantly restored its expression in 9 (75%) of these 12 cell lines. HAI-2 was found to be frequently underexpressed in human HCCs (p < 0.001). With bisulphite DNA sequencing and methylation-specific PCR, we found that the promoter of the HAI-2 gene was frequently hypermethylated in both HCC cell lines and human HCCs. Ectopic expression of HAI-2 significantly inhibited cell migration and invasiveness of HCC cells in vitro and suppressed tumourigenicity in vivo. In addition, we also provided the first evidence that HAI-2 mediated its tumour suppressor function via the Kunitz domain 1 (KD-1), as KD-1 but not KD-2 inactivating mutant abolished its anti-tumour invasiveness in vitro. Our findings suggest that HAI-2 is a candidate tumour suppressor gene that is frequently hypermethylated and underexpressed in human HCCs, and the KD-1 domain of HAI-2 is the key region responsible for its anti-invasive function. © 2008 Wiley-Liss, Inc.en_HK
dc.languageengen_HK
dc.publisherJohn Wiley & Sons, Inc.. The Journal's web site is located at http://www3.interscience.wiley.com/journal/29331/homeen_HK
dc.relation.ispartofInternational Journal of Canceren_HK
dc.rightsInternational Journal of Cancer. Copyright © John Wiley & Sons, Inc.en_HK
dc.subjectEpigeneticsen_HK
dc.subjectHAI-2en_HK
dc.subjectHCCen_HK
dc.subjectKunitz domainen_HK
dc.subjectSerine protease inhibitoren_HK
dc.subject.meshAdulten_HK
dc.subject.meshAgeden_HK
dc.subject.meshCarcinoma, Hepatocellular - genetics - metabolismen_HK
dc.subject.meshCell Line, Tumoren_HK
dc.subject.meshDown-Regulationen_HK
dc.subject.meshEpigenesis, Geneticen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshGene Expression Regulation, Neoplasticen_HK
dc.subject.meshHumansen_HK
dc.subject.meshLiver Neoplasms - genetics - metabolismen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMembrane Glycoproteins - genetics - metabolismen_HK
dc.subject.meshMiddle Ageden_HK
dc.subject.meshNeoplasm Invasivenessen_HK
dc.subject.meshProtein Structure, Tertiaryen_HK
dc.titleHAI-2 is epigenetically downregulated in human hepatocellular carcinoma, and its Kunitz domain type 1 is critical for anti-invasive functionsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0020-7136&volume=124&spage=1811&epage=&date=2009&atitle=HAI-2+is+epigenetically+downregulated+in+human+hepatocellular+carcinoma,+and+its+Kunitz+domain+type+1+is+critical+for+anti-invasive+functions.+en_HK
dc.identifier.emailWong, CM:jackwong@pathology.hku.hken_HK
dc.identifier.emailChing, YP:ypching@hku.hken_HK
dc.identifier.emailNg, IOL:iolng@hkucc.hku.hken_HK
dc.identifier.authorityWong, CM=rp00231en_HK
dc.identifier.authorityChing, YP=rp00469en_HK
dc.identifier.authorityNg, IOL=rp00335en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/ijc.24115en_HK
dc.identifier.pmid19107935-
dc.identifier.scopuseid_2-s2.0-62449253973en_HK
dc.identifier.hkuros155429en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-62449253973&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume124en_HK
dc.identifier.issue8en_HK
dc.identifier.spage1811en_HK
dc.identifier.epage1819en_HK
dc.identifier.isiWOS:000264452700009-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridTung, EKK=7003519614en_HK
dc.identifier.scopusauthoridWong, CM=16314668400en_HK
dc.identifier.scopusauthoridYau, TO=7006540669en_HK
dc.identifier.scopusauthoridLee, JMF=36065603500en_HK
dc.identifier.scopusauthoridChing, YP=7005431277en_HK
dc.identifier.scopusauthoridNg, IOL=7102753722en_HK

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