[Telomerase, cell immortality and cancer]

Telomerase is an enzyme that replaces repetitive (TTAGGG)n sequences on the ends of chromosomes that would otherwise be lost during successive cell divisions. Telomerase activity is closely linked to attainment of cellular immortality, a step in carcinogenesis, while lack of such activity contributes to cellular senescence. Telomerase is activated in more than 85% of malignant tumors. However, with the exception of some self-renewing tissues with high regenerative potential, telomerase activity is usually repressed in normal somatic tissues. Based on these reports, we investigated telomerase activity in gastric mucosal tissues. Telomerase activity is highest in cancer, followed by intestinal metaplasia, chronic gastritis, and normal mucosa. In patients with intestinal-type gastric cancer, telomerase activity was higher in those with intestinal metaplasia and H. pylori infection than in patients without infection. Our results suggest that H. pylori infection may influence telomerase activity in cancer and noncancerous tissue. Genes encoding three major components of human telomerase have been recently cloned. They included those for human telomerase RNA component (hTR), human telomerase reverse transcriptase (hTERT), and telomerase-associated protein 1 (TEP1). More recently, two human telomeric repeat binding factors (TRFs) have also been cloned: TRF1, considered to inhibit the action of telomerase at the telomeric region, and TRF2, believed to prevent fusion of chromosome ends and, in vitro, to remodel linear telomeric DNA into large duplex loops. However, the details of mechanisms regulating telomerase activity are still poorly understood, and specific components or binding proteins that might represent suitable targets for cancer gene therapy have not yet been identified. Therefore, we established quantitative assays using a TaqMan RT-PCR for mRNAs encoding the telomerase components hTR, hTERT, and TEP1, as well as for those encoding TRF1 and TRF2. By using our quantitative assays, we found the following results: 1) Expression of TRF1 and TRF2 mRNA was greater in the normal cells than in human malignant hematopoietic cell lines or in patients with acute leukemia, 2) hTERT mRNA expression showed changes paralleling telomerase activity and became undetectable with HL60 cell differentiation, 3) initially low expression of TRF1 and TRF2 mRNA increased during differentiation. Our results suggest that not only hTERT but also TRF1 and 2 are important regulators of telomerase activity.