Site-specific methylation of CpG nucleotides in the hTERT promoter region can control the expression of hTERT during malignant progression of colorectal carcinoma

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Abstract

Expression of hTERT has been recognized an important factor in cellular aging and immortalization. Therefore, to analyze regulatory mechanism of hTERT expression, we investigated the CpG methylation pattern of the hTERT promoter as an epigenetic mechanism and its implication in transcriptional regulation of hTERT using tissues of colorectal carcinoma. As a result, we were able to observe an increased pattern of hTERT expression according to the malignant progression of colorectal carcinoma. Additionally, we could find that hTERT expression was induced when the P1 and P2 region of hTERT were sufficiently hypermethylated and, oppositely, the G1 region of hTERT was hypomethylated. Importantly, we could find three specific CpG sites (7th CpG of P2 and 11th and 2nd–10th CpGs of P1) closely related with the increasing of hTERT expression. These findings may provide important clues to deducing the expression mechanisms of hTERT.

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Materials and methods

Patients, specimens, and cell lines. We analyzed 22 colorectal carcinoma tissues, five colon normal tissues, and the HCT 116 colon cancer cell line. These tissues of colorectal carcinoma and normal mucosa of 22 patients were obtained by surgical resection. All patients were diagnosed pathologically and no patient received radiotherapy or chemotherapy before the sampling. The samples were examined histologically for the presence of tumor cells. Clinical staging showed Duke’s A in one case,

hTERT expression in colorectal carcinomas is closely related with malignant progression

Recent investigations have demonstrated that hTERT activity is significantly increased in human malignant tumors, but is not expressed in normal somatic cells. Moreover, the quantification of hTERT expression holds promise for cancer prognosis as high telomerase activity has been correlated with a poor prognosis for a number of cancers [2], [3], [4], [17]. This suggests that hTERT activity and progression of malignant tumors are closely related.

Therefore, in our study, we investigated whether

Acknowledgment

This work was supported by Grants (R01-2004-000-10375-0) from the Korea Science and Engineering Foundation.

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    Citation Excerpt :

    A direct correlation between hTERT promoter methylation and gene expression was first reported by Guilleret et al. (2002). Specifically, a certain part of the promoter and/or the proximal exonic region must be hypomethylated for hTERT transcription to take place (Guilleret and Benhattar, 2004; Choi et al., 2007). USSC cells do not exhibit telomerase activity despite their extensive proliferative capacity in vitro.

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