Positive Regulation of Human Telomerase Reverse Transcriptase Gene Expression and Telomerase Activity by DNA Methylation in Pancreatic Cancer
- 201 Downloads
We sought to determine the role of telomerase and its catalytic subunit hTERT in pancreatic cancer and evaluate the epigenetic regulation of hTERT by promoter methylation.
Thirty paired samples of pancreatic ductal adenocarcinomas and adjacent normal tissue and 12 chronic pancreatitis samples were studied. Reverse transcriptase polymerase chain reaction, telomeric repeat amplification protocol assay, and methylation-specific polymerase chain reaction were performed to analyze hTERT expression, telomerase activity, and methylation status of gene promoters, respectively.
hTERT and telomerase activity were upregulated in pancreatic cancer compared with paired normal tissues and samples of pancreatitis. hTERT expression correlated with telomerase activity (P < .05) and in turn correlated positively with hTERT promoter methylation (P < .001) and p16 promoter methylation. hTERT transcript expression and telomerase activity both conferred a worse outcome by univariate and multivariate analysis (P < .05).
hTERT expression and telomerase activity are predictors of poor outcome in pancreatic cancer. hTERT gene expression is positively regulated by promoter methylation.
KeywordsPancreatic Cancer Chronic Pancreatitis Promoter Methylation Pancreatic Ductal Adenocarcinoma hTERT mRNA
A.K. was supported by Council of Scientific and Industrial Research, New Delhi, India in the form of fellowship, grant 9/141(154)-EMR-2003.
- 6.Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. 2nd ed. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1989.Google Scholar
- 17.Kumari A, Srinivasan R, Wig JD. Effect of C-MYC and E2F1 gene silencing and of 5-Azacytidine treatment on telomerase activity in pancreatic cancer derived cell lines. Pancreatology. (in press).Google Scholar
- 18.Zhu Q, Liu C, Ge Z, et al. Lysine-specific demethylase 1 (LSD1) is required for the transcriptional repression of the telomerase reverse transcriptase (hTERT) gene. PLoS One. 2008;3:e1446.Google Scholar
- 23.Kyo S, Takakura M, Kanaya T, et al. Estrogen activates telomerase. Cancer Res. 2000;59:5917–21.Google Scholar
- 26.Soriano A, Castells A, Ayuso JR, et al. Preoperative staging and tumor respectability assessment of pancreatic cancer: prospective study comparing endoscopic ultrasonographc, helical computed tomography, magnetic resonance imaging and angiography. Am J Gastroenterol. 2004;99:492–501.PubMedCrossRefGoogle Scholar