| Summary: | 碩士 === 中山醫學大學 === 醫學分子毒理學研究所 === 98 === Telomeres consist of tandem oligonucleotide repeats (5’-TTAGGG-3’) that cap the ends of eukaryotic chromosomes to prevent further degradation and loss of human essential gene. Functional Telomeres are also essential for continued cell proliferation. By present research report, telomeres progressively shorten during each cell division without increasing the telomerase activity in most human cell. However, tumor cell generally have functional and short telomere lengths and revealed upregulated telomerase activity. Therefore, telomerase activity is hallmarks of tumorgenesis.
On the other hand, DNA methylation and histone acetylation are important mechanism of epigenetic regulation without affecting the DNA sequence. Our in vitro and in vivo experiences tried to prove the relationship between telomerase activity and the methylation or histone acetylation of promoter region in human telomerase reverse transcriptase (hTERT).
5-Aza-2’-deoxycytidine (5-aza-dC) and Trichostatin A (TSA) are both added into the culture medium of two human non-small cell lung cancer cell line (H1299 and A549). Demethylating agent (5-aza-dC) activated the hTERT mRNA expression in H1299 and A549 cell lines. However, the TSA repressed the hTERT mRNA expression and telomerase activity in H1299 and A549 cell lines. TSA targets c-Myc and Ets-2 binding sites within the core region of the hTERT promoter to suppress the telomerase activity of H1299 and A549 cell lines.
Genomic DNAs were extracted from non-small cell lung cancer samples and adjacent normal lung tissue of 62 patients. Hypermethylation status of the promoter of hTERT was found in low expressed hTERT of tumor sample and adjacent normal lung tissue (p=0.029 and p=0.01). Extremely shortened telomere length in tumor sample than adjacent normal lung tissue without correlated with the methylation status of promoter of hTERT and telomerase activity also noted in our experience.
Base on these two experiences, the data show that the methylation and histone acetylation status in core promoter of hTERT could control the expression of hTERT and further telomerase activity. However, we can’t demonstrate that they could be potential biologic marker targets for clinical outcome of non-small cell lung cancer patients.
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