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Conference Paper: Dysregulation of Mitotic Spindle Checkpoint Control in Hepatocellular Carcinomas

TitleDysregulation of Mitotic Spindle Checkpoint Control in Hepatocellular Carcinomas
Authors
Issue Date2004
PublisherAmerican Association for Cancer Research
Citation
AACR 95th Annual Meeting, Orlando FL, 27–31 March 2004. In Cancer Research, 2004, v. 64 n. 7S, p. 184 Abstract no. 798 How to Cite?
AbstractChromosomal instability (CIN) refers to high rates of chromosome gains and losses and is a major cause of genomic instability. Recurrent chromosome alterations have been commonly found in hepatocellular carcinoma (HCC), which is a prevalent cancer worldwide and in Southeast Asia and Hong Kong. These frequent gains and losses of chromosomes suggest that CIN contributes to hepatocarcinogenesis. One major mechanism for CIN is through the loss of mitotic checkpoint. In this study, we evaluated mitotic spindle checkpoint competence in HCC cell lines, using nocodazole and colcemid, which inhibit spindle assembly. Six of the eleven HCC cell lines tested showed a defect in mitotic competency. In addition, these six HCC cell lines also showed a reduction in the expression of a major mitotic checkpoint protein, called Mitotic Arrest Deficient 2 (MAD2). This association of mitotic spindle checkpoint incompetence and the downregulation of MAD2 protein in these HCC cells suggest that deficiency of the MAD2 protein may play a role in mitotic spindle checkpoint defect in HCC. In addition to MAD2, we have also examined the expression of MAD1, the binding partner of MAD2, which also plays an important role in the progression of mitosis. During the evaluation of MAD1 expression, we have identified a novel splicing variant of MAD1, which we named MAD1β. This isoform was detected in all HCC cell lines tested and in most of the human HCC samples and their corresponding nontumorous livers. Upon sequencing, we found that MAD1β had no exon 4, which was likely a result of different splicing. In addition, with confocal microscopy, overexpression of MAD1β in HCC cell lines resulted in a different subcellular localization (cytoplasmic) as compared with that of MAD1 (nuclear). These results suggest that exon 4 may contain a nuclear localization signal which can regulate the localization of MAD1 protein in cells. Overall, our results suggest that reduced MAD2 expression may contribute to mitotic checkpoint defect in HCC. In addition, further investigation into this newly identified MAD1 isoform, MAD1β, is warranted.
Persistent Identifierhttp://hdl.handle.net/10722/96049
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372

 

DC FieldValueLanguage
dc.contributor.authorSze, MFen_HK
dc.contributor.authorChing, YPen_HK
dc.contributor.authorJin, Den_HK
dc.contributor.authorNg, IOLen_HK
dc.date.accessioned2010-09-25T16:21:46Z-
dc.date.available2010-09-25T16:21:46Z-
dc.date.issued2004en_HK
dc.identifier.citationAACR 95th Annual Meeting, Orlando FL, 27–31 March 2004. In Cancer Research, 2004, v. 64 n. 7S, p. 184 Abstract no. 798-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/96049-
dc.description.abstractChromosomal instability (CIN) refers to high rates of chromosome gains and losses and is a major cause of genomic instability. Recurrent chromosome alterations have been commonly found in hepatocellular carcinoma (HCC), which is a prevalent cancer worldwide and in Southeast Asia and Hong Kong. These frequent gains and losses of chromosomes suggest that CIN contributes to hepatocarcinogenesis. One major mechanism for CIN is through the loss of mitotic checkpoint. In this study, we evaluated mitotic spindle checkpoint competence in HCC cell lines, using nocodazole and colcemid, which inhibit spindle assembly. Six of the eleven HCC cell lines tested showed a defect in mitotic competency. In addition, these six HCC cell lines also showed a reduction in the expression of a major mitotic checkpoint protein, called Mitotic Arrest Deficient 2 (MAD2). This association of mitotic spindle checkpoint incompetence and the downregulation of MAD2 protein in these HCC cells suggest that deficiency of the MAD2 protein may play a role in mitotic spindle checkpoint defect in HCC. In addition to MAD2, we have also examined the expression of MAD1, the binding partner of MAD2, which also plays an important role in the progression of mitosis. During the evaluation of MAD1 expression, we have identified a novel splicing variant of MAD1, which we named MAD1β. This isoform was detected in all HCC cell lines tested and in most of the human HCC samples and their corresponding nontumorous livers. Upon sequencing, we found that MAD1β had no exon 4, which was likely a result of different splicing. In addition, with confocal microscopy, overexpression of MAD1β in HCC cell lines resulted in a different subcellular localization (cytoplasmic) as compared with that of MAD1 (nuclear). These results suggest that exon 4 may contain a nuclear localization signal which can regulate the localization of MAD1 protein in cells. Overall, our results suggest that reduced MAD2 expression may contribute to mitotic checkpoint defect in HCC. In addition, further investigation into this newly identified MAD1 isoform, MAD1β, is warranted.-
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Research-
dc.relation.ispartofCancer Researchen_HK
dc.titleDysregulation of Mitotic Spindle Checkpoint Control in Hepatocellular Carcinomasen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailSze, MF: szekaren@yahoo.comen_HK
dc.identifier.emailChing, YP: ypching@hkucc.hku.hken_HK
dc.identifier.emailJin, D: dyjin@hkucc.hku.hken_HK
dc.identifier.emailNg, IOL: iolng@hkucc.hku.hken_HK
dc.identifier.authorityChing, YP=rp00469en_HK
dc.identifier.authorityJin, D=rp00452en_HK
dc.identifier.authorityNg, IOL=rp00335en_HK
dc.identifier.hkuros148230en_HK

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