Aberrant methylation of EDNRB and p16 genes in hepatocellular carcinoma (HCC) in Taiwan.

Epigenetic alternation via the promoter hypermethylation of putative tumor suppressor genes has been implicated in the development of hepatocellular carcinoma (HCC). In this study, we investigated the epigenetic changes in two candidate tumor suppressor genes, endothelin receptor type B (EDNRB) and p16, and their relation to the expression of these two genes in HCC. Methylation-specific polymerase chain reaction (MS-PCR) was performed to analyze the promoter methylation status of the EDNRB and p16 genes in tumors and paired non-tumor liver portions of 34 HCC patients. The mRNA expression was assessed by reverse transcription-PCR assay. Hypermethylation of the EDNRB and p16 genes was detected in 29.4% (10/34) and 32.3% (11/34) of HCC patients, respectively. Moreover, the reduction of mRNA expression was correlated to the promoter hypermethylation of the EDNRB and p16 genes. In conclusion, aberrant methylation of EDNRB and p16 genes is highly prevalent in HCC. It suggested that epigenetic alteration of the EDNRB and p16 genes may play an important role in the pathogenesis of HCC.

[1]  S. Thibodeau,et al.  hMLH1 and hMSH2 expression in human hepatocellular carcinoma. , 2001, International journal of oncology.

[2]  J. Christman,et al.  5-Azacytidine and 5-aza-2′-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy , 2002, Oncogene.

[3]  Yang Qin,et al.  Association of low p16INK4a and p15INK4b mRNAs expression with their CpG islands methylation with human hepatocellular carcinogenesis. , 2004, World journal of gastroenterology.

[4]  W. Yeo,et al.  Silencing of GSTP1 gene by CpG island DNA hypermethylation in HBV-associated hepatocellular carcinomas. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[5]  Hoguen Kim,et al.  p16 is a major inactivation target in hepatocellular carcinoma , 2000, Cancer.

[6]  Chien-Jen Chen,et al.  High frequency of promoter hypermethylation of RASSF1A and p16 and its relationship to aflatoxin B1–DNA adduct levels in human hepatocellular carcinoma , 2002, Molecular carcinogenesis.

[7]  G. Liang,et al.  The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cells. , 2001, Human molecular genetics.

[8]  Y. Takeshima,et al.  Inactivation of the p16 gene by hypermethylation and loss of heterozygosity in adenocarcinoma of the lung , 2004, Pathology international.

[9]  M. Fukayama,et al.  High‐density methylation of p14ARF and p16INK4A in Epstein‐Barr virus–associated gastric carcinoma , 2004, International journal of cancer.

[10]  J. Schlesselman,et al.  Methylation of multiple genes in prostate cancer and the relationship with clinicopathological features of disease. , 2004, Oncology reports.

[11]  J. Sheu,et al.  Infrequent mutations and no methylation of CDKN2A (P16/MTS1) and CDKN2B (p15/MTS2) in hepatocellular carcinoma in Taiwan. , 1998, European journal of cancer.

[12]  E. Yu,et al.  p16 Hypermethylation in the early stage of hepatitis B virus-associated hepatocarcinogenesis. , 2003, Cancer letters.

[13]  W. Lau,et al.  High frequency of p16INK4A gene alterations in hepatocellular carcinoma , 1999, Oncogene.

[14]  M. Ozturk.  Genetic Aspects of Hepatocellular Carcinogenesis , 1999, Seminars in liver disease.

[15]  J. Tangrea,et al.  A survey of gene-specific methylation in human prostate cancer among black and white men. , 2004, Cancer letters.

[16]  L. Larue,et al.  Involvement of endothelin receptors in normal and pathological development of neural crest cells. , 2003, The International journal of developmental biology.

[17]  M. Buendia,et al.  Altered expression of E‐cadherin in hepatocellular carcinoma: Correlations with genetic alterations, β‐catenin expression, and clinical features , 2002, Hepatology.

[18]  D. Ellison,et al.  Identification of tumour-specific epigenetic events in medulloblastoma development by hypermethylation profiling. , 2003, Carcinogenesis.

[19]  M. Yamamoto,et al.  Genetic and epigenetic events in human hepatocarcinogenesis. , 2001, International journal of oncology.

[20]  G. Kang,et al.  Correlation of methylation of the hMLH1 promoter with lack of expression of hMLH1 in sporadic gastric carcinomas with replication error. , 1999, Laboratory investigation; a journal of technical methods and pathology.

[21]  S N Thibodeau,et al.  Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. , 1998, Cancer research.

[22]  W. Coleman,et al.  Mechanisms of human hepatocarcinogenesis. , 2003, Current molecular medicine.

[23]  Hyeon Joo Lee,et al.  Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. , 2003, The American journal of pathology.

[24]  P. Campos,et al.  Endothelin B receptor gene hypermethylation in prostate adenocarcinoma , 2003, Journal of clinical pathology.

[25]  Wen-Jeng Wu,et al.  Genetic alterations of p16INK4a and p14ARF genes in human bladder cancer. , 2003, The Journal of urology.

[26]  J. Herman,et al.  DNA hypermethylation in tumorigenesis: epigenetics joins genetics. , 2000, Trends in genetics : TIG.

[27]  Ya‐Wen Cheng,et al.  Frequent p16INK4a promoter hypermethylation in human papillomavirus‐infected female lung cancer in Taiwan , 2005, International journal of cancer.

[28]  J. Heighway,et al.  Decreased endothelin receptor B expression in large primary uveal melanomas is associated with early clinical metastasis and short survival , 2002, British Journal of Cancer.

[29]  Tsuyoshi Saito,et al.  Mechanisms of inactivation of the p16INK4a gene in leiomyosarcoma of soft tissue: decreased p16 expression correlates with promoter methylation and poor prognosis , 2003, The Journal of pathology.

[30]  成松 孝.  p16 promoter hypermethylation in human hepatocellular carcinoma with or without hepatitis virus infection , 2004 .

[31]  P. Puri,et al.  Altered endothelin-3 and endothelin-B receptor mRNA expression in Hirschsprung's disease. , 1999, Journal of pediatric surgery.

[32]  Nita Ahuja,et al.  DNA methylation and environmental exposures in human hepatocellular carcinoma. , 2002, Journal of the National Cancer Institute.

[33]  G. Hannon,et al.  A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 , 1993, Nature.

[34]  G. Liang,et al.  Novel endothelin B receptor transcripts with the potential of generating a new receptor. , 1999, Gene.

[35]  J. Herman,et al.  Aberrant promoter methylation profiles of tumor suppressor genes in hepatocellular carcinoma. , 2003, The American journal of pathology.

[36]  M. Toyota,et al.  Detection of hypermethylation of thep16INK4A gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus , 2001, Gut.

[37]  J. Herman,et al.  Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Kwong,et al.  Promoter hypermethylation of the EDNRB gene in nasopharyngeal carcinoma , 2002, International journal of cancer.

[39]  Jeanne Kowalski,et al.  Hypermethylation of CpG Islands in Primary and Metastatic Human Prostate Cancer , 2004, Cancer Research.