HUMAN TELOMERASE REVERSE-TRANSCRIPTASE AS A CRITICAL DETERMINANT OF TELOMERASE ACTIVITY IN NORMAL AND MALIGNANT ENDOMETRIAL TISSUES

Telomerase activation is thought to be essential for cellular immortal ity and oncogenesis, It is observed in most malignant tumors but not i n most normal somatic tissues. Normal human endometrium is, however, k nown to express significant telomerase activity in a menstrual phase-d ependent manner, The 3 major subunits composing telomerase have been i dentified, Using normal and malignant endometrial tissues, we studied how these components are involved in telomerase activation. A total of 23 endometrial cancers and 32 normal human endometria in various mens trual phases as well as cell lines derived from endometrial cancer wer e examined for the expression of each telomerase subunit using RT-PCR analysis. Telomerase activity in each sample was determined by the TRA P assay, and the correlation between subunit expression and telomerase activity was examined. RT-PCR analysis revealed that telomerase RNA ( hTR) and telomerase-associated protein (TP I) mRNA were constitutively expressed in both normal and malignant endo metrial tissues. Expressi on of human telomerase reverse transcriptase (hTERT) mRNA was observed in most endometrial cancers, while that in normal endometrium depende d on the phases of menstrual cycles. Proliferative phase normal endome tria expressed hTERT mRNA, while secretory phase endometria did not. T here was a strong association between telomerase activity and hTERT ex pression but not TPI or hTR expression in both normal and tumor tissue s. Five telomerase-positive endometrial cancer cell lines expressed ea ch of the telomerase subunits including hTERT, while 2 telomerase-nega tive normal primary fibroblast cells expressed TPI mRNA and hTR, but n ot hTERT mRNA, Our findings suggest that hTERT is a rate-limiting dete rminant of enzymatic activity of human telomerase, Since some normal t issues with high regenerative potential can express hTERT, special att ention should be paid to the clinical use of hTERT inhibitors as anti- cancer drugs, (C) 1999 Wiley-Liss. Inc.