Carcinogenesis Advance Access originally published online on January 27, 2005
Carcinogenesis 2005 26(4):855-863; doi:10.1093/carcin/bgi011
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Carcinogenesis vol.26 no.4 © Oxford University Press 2005; all rights reserved.
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Epigenetic and genetic alterations of p33ING1b in ovarian cancer
1 Department of Pathology, People's Hospital, Peking University, Beijing, Republic of China, 2 Department of Pathology, S.H. Ho Foundation Research Laboratories in Pathology, and 3 Department of Obstetrics and Gynecology, Hong Kong Jockey Club Clinical Research Centre, The University of Hong Kong, Hong Kong, Republic of China
* To whom correspondence should be addressed at: Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, Republic of China. Tel: +852 28554876; Fax: +852 28725197; Email: anycheun{at}hkucc.hku.hk
p33ING1b is a candidate tumor suppressor gene and a nuclear protein. We investigated whether genetic and epigenetic mechanisms affect p33ING1b expression in ovarian cancer thus contributing toward its pathogenesis. A total of 111 ovarian cancers collected from Beijing and Hong Kong were used for this study. Weak or negative p33ING1b protein expression was demonstrated by immunohistochemistry on tissue microarray in 28/111 cases. Real-time quantitative RT–PCR also showed overall significant reduction of p33ING1b mRNA expression (P = 0.0137), with 53.1% (17/32) cases showing 2- to 5-fold reduction and absence of expression. The reduction of mRNA expression in cancer correlated with decreased p33ING1b protein expression (P < 0.0001). While no p33ING1b mutation was found, allelic loss at the p33ING1b locus was demonstrated in 25% (8/32) cases. The allelic loss profiles also showed statistical significant correlation with reduction of p33ING1b protein and mRNA expression (P = 0.031 and 0.030). Promoter methylation as assessed by methylation specific PCR was found in 23.9% (21/88) cases analyzed. Bisulfite sequencing results confirmed the p33ING1b promoter methylation status of these methylation positive cases. Statistical significant correlation between methylation and mRNA expression (P = 0.006) was demonstrated. Treatment with demethylating drug, 5'-aza-2'-deoxycytidine, resulted in dosage-dependent elevated mRNA expression of p33ING1b in ovarian cancer cell lines. This is the first study reporting epigenetic mechanism regulating the p33ING1b expression. Our findings support that genetic and epigenetic alteration of p33ING1b are likely to contribute towards the pathogenesis of ovarian cancers.
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