Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0476089 (endometrial cancer)
11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Telomerase activation is thought to be essential for cellular immortality and oncogenesis. It is observed in most malignant tumors but not in most normal somatic tissues. Normal human endometrium is, however, known to express significant telomerase activity in a menstrual phase-dependent manner. The 3 major subunits composing telomerase have been identified. 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 menstrual phases as well as cell lines derived from endometrial cancer were examined for the expression of each telomerase subunit using RT-PCR analysis. Telomerase activity in each sample was determined by the TRAP assay, and the correlation between subunit expression and telomerase activity was examined. RT-PCR analysis revealed that telomerase RNA (hTR) and telomerase-associated protein (TP1) mRNA were constitutively expressed in both normal and malignant endometrial tissues. Expression of human telomerase reverse transcriptase (hTERT) mRNA was observed in most endometrial cancers, while that in normal endometrium depended on the phases of menstrual cycles. Proliferative phase normal endometria expressed hTERT mRNA, while secretory phase endometria did not. There was a strong association between telomerase activity and hTERT expression but not TP1 or hTR expression in both normal and tumor tissues. Five telomerase-positive endometrial cancer cell lines expressed each of the telomerase subunits including hTERT, while 2 telomerase-negative normal primary fibroblast cells expressed TP1 mRNA and hTR, but not hTERT mRNA. Our findings suggest that hTERT is a rate-limiting determinant of enzymatic activity of human telomerase. Since some normal tissues with high regenerative potential can express hTERT, special attention should be paid to the clinical use of hTERT inhibitors as anti-cancer drugs.
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PMID:Human telomerase reverse transcriptase as a critical determinant of telomerase activity in normal and malignant endometrial tissues. 993 31

Seventeen patients with endometrial cancer were studied. Tissues of primary (P) and metastatic (M) lesions were obtained from 8 patients and complete sets of P, M and Recurrent (R) lesions were obtained from 9 patients during a follow-up period of 1-10 years. Expressions of estrogen receptors, progesterone receptors, multidrug resistance protein-1, multidrug resistance-related protein, c-erbB-2, membrane-type metalloproteinase, human telomerase RNA, human telomerase reverse transcriptase RNA, E-cadherin and autocrine motility factor receptor were studied by RT-PCR. Also, telomeric restriction fragment length (TRFL) and microsatellite instability were determined between P, M and R. The results indicate that there are significant differences in the gene expression frequency during tumor progression. The mismatch rate ranged from 0 to 47.1% between P and M and from 14.3% to 66.7% between P and R, respectively. The TRFL analysis showed a marked reduction in P and M (P vs. M: 8.2 +/- 0.9 vs. 5.6 +/- 0.4 kb, mean +/-SEM, n = 9, p = 0.002 by paired Student's t test). The length further decreased in R (P vs. R: 8.2 +/- 0.9 vs. 3.2 +/- 0.7, p = 0.01, M vs. R: 5.6 +/- 0.4 vs. 3.2 +/- 0.7, p = 0.005). The genomic instability/replication error was tested by AluI arbitrary primed polymerase chain reaction (AP-PCR). Five out of 17 patients showed an altered replication error pattern (29.4%). The mean number of abnormal AluI AP-PCR patterns in M and R compared to the P was 1.5 (M) and 4 (R). The difference between the P and R was statistically significant (p < 0.04). The present data indicate that biological behavior of cancer cells in P, M and R may differ significantly.
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PMID:Gene expression in primary, metastatic and recurrent lesions of endometrial cancer. 1054 51

Emerging evidence indicates that sex steroid hormones regulate telomerase in target tissues. We have reported that estrogen activates telomerase through transactivation of the telomerase catalytic subunit, human telomerase reverse transcriptase (hTERT). Progesterone usually antagonizes estrogen action in reproductive organs, but the effect on telomerase remains unclear. In this study, we examine the effects of progesterone on the gene expression of hTERT in breast and endometrial cancer cell lines expressing progesterone receptor. Progesterone significantly induced hTERT mRNA expression within 3 h after exposure. This transient effect peaked at 12 h and then decreased. In contrast, exposure to progesterone for > 48 h antagonized estrogen effects and inhibited the estrogen-induced activation of hTERT expression; the cyclin-dependent kinase inhibitor p21/Waf1/Cip1 plays an integral role in this inhibition. Thus, progesterone exerts diverse effects on hTERT mRNA expression in a time-dependent manner. We also found that the mitogen-activated protein kinase signaling pathway mediates both the short-term and long-term effects of progesterone on hTERT gene expression. These findings support the notion that hTERT gene is a target of both estrogen and progesterone.
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PMID:Progesterone regulates human telomerase reverse transcriptase gene expression via activation of mitogen-activated protein kinase signaling pathway. 1103 74

Three major components of telomerase, i.e., human telomerase RNA (hTERC), telomerase-associated protein (TEP1), and the human telomerase reverse transcriptase (hTERT), have been identified. Among them, TERT expression is very closely related to telomerase activity. The purpose of this study was to evaluate the implications of TERT expression and telomerase activity in endometrial cancer. Fresh surgical specimens of 36 endometrial carcinomas (CA group) and 9 samples of postmenopausal endometrial tissue without malignancy (NP group) were obtained at operation in our hospital. These specimens were analyzed for telomerase activity and TERT expression by TRAP assay and RT-PCR, respectively, and the detection and quantitative analysis were made. The results for endometrial cancer were compared with those for normal endometrium and with the clinical data. In the CA group, TERT expression was detected in 35/36 subjects (97.2%), whereas in 1/9 subject (11.1%) from the NP group. Relative TERT mRNA expression was 0.50 in the CA group, and this was significantly higher compared with the level of 0.10 in the NP group (p<0.05). Telomerase activity was detected in 34/36 subjects (94.4%) from the CA group and in 3/9 subjects (33.3%) from the NP group (p<0.05), while the RTA was 30.9 and 0.2, respectively (p<0.05). There was a significant correlation between the relative TERT expression and RTA (n=45, R=0.413, p<0.05). RTA was significantly higher at an advanced surgical stage (FIGO II, III or IV) than at an early stage (FIGO 0 or I) (52.4 vs. 20.4, p<0.05), but other clinical factors showed no relationship with TERT and RTA values. The detection and quantitative analysis of telomerase activity and TERT expression is helpful for distinguishing malignant from normal endometrium when the patient is postmenopausal, even if the tumor is very small or of low malignancy.
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PMID:Expression of telomerase reverse transcriptase mRNA and its quantitative analysis in human endometrial cancer. 1107 9

A herbal complex consisting of Hoelen, Angelicae radix, Scutellariae radix and Glycyrrhizae radix suppressed cell viability and telomerase activity in hormone-refractory and chemo-resistant cancer cell lines, namely poorly differentiated uterine endometrial cancer cell line AN3 CA, adriamycin-resistant breast cancer cell line MCF7/ADR and cisplatin-resistant ovarian cancer cell line A2780. Furthermore, the herbal complex suppressed the expression of the full length of human telomerase reverse transcriptase (hTERT), which is related to telomerase activity. This indicates that the herbal complex can suppress the tumor growth of chemoendocrine resistant cancers, at least in part via suppression of telomerase activity associated with down-regulated hTERT.
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PMID:Herbal complex suppresses telomerase activity in chemo-endocrine resistant cancer cell lines. 1176 37

Tamoxifen is widely applied as an antiestrogenic agent for adjuvant therapy in the treatment of breast cancer, while its estrogen-agonistic activity occasionally causes proliferative disorders or carcinogenesis at other sites, such as the uterus. We reported that estrogen activates telomerase in breast and endometrial cancer cells. The present study examines the effects of tamoxifen on the gene expression of human telomerase reverse transcriptase (hTERT) in breast and endometrial cancer cells. Tamoxifen inhibited the cell growth of MCF-7 cells, as well as hTERT mRNA expression in the presence of estrogen (E2), antagonizing the E2 effects. In contrast, tamoxifen stimulated the growth of Ishikawa cells and activated hTERT mRNA expression in the absence or presence of E2, exhibiting estrogen-agonistic action. Transient expression assays revealed that these actions of tamoxifen are achieved by transcriptional regulation of the hTERT promoter. An estrogen responsive element (ERE) in the hTERT 5' regulatory region was partly responsible for both the E2-antagonistic and -agonistic actions of tamoxifen. Tamoxifen activated the MAP kinase cascade in Ishikawa cells, but not in MCF-7 cells, and the activation of hTERT mRNA expression was effectively blocked by MEK inhibitor, suggesting that the MAP kinase pathway is involved in the tamoxifen-induced activation of hTERT. These findings indicate that tamoxifen regulates hTERT expression in a cell-type specific manner. Tamoxifen-induced activation of hTERT may be one component of estrogen agonistic function of tamoxifen that is involved in endometrial carcinogenesis induced by this agent.
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PMID:Tamoxifen regulates human telomerase reverse transcriptase (hTERT) gene expression differently in breast and endometrial cancer cells. 1203 53

We investigated the relationship between the antiproliferative effect of GnRH agonist and telomerase activity using the endometrial cancer cell line HEC-1A. The subjects were 38 endometrial cancer, and 2 atypical endometrial hyperplasia patients. GnRH-R expression was detected using RT-PCR. HEC-1A cells were incubated with 10(-7)-10(-4) M GnRH agonist (leuprolide acetate), and cell proliferation was determined using MTT assay. The telomerase activity was detected by the TRAP assay and expression of human telomerase reverse transcriptase (hTERT) was assessed by RT-PCR. GnRH-R mRNA was detected at 94.7% (36/38) in endometrial cancer and in both of the atypical endometrial hyperplasia and in HEC-1A cells. Cell proliferation of HEC-1A showed significant inhibition at leuprolide acetate concentrations of 10(-6) M or higher compared with untreated control culture (p<0.05). The telomerase activity showed no marked difference compared with untreated culture. However, hTERT mRNA expression showed a decrease in the leuprolide-treated cells. It is suggested that the mechanism of the antitumor effect of GnRH agonist involved the inhibition of hTERT mRNA expression in the endometrial cancer cells.
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PMID:GnRH agonist inhibits human telomerase reverse transcriptase mRNA expression in endometrial cancer cells. 1237 98

This study evaluated the immunohistochemical expression of human telomerase reverse transcriptase (hTERT) in endometrial carcinoma and atypical endometrial hyperplasia, and related it to the expression of topoisomerase (TP)IIalpha (a proliferation associated enzyme); apoptosis as determined by the frequency of apoptotic bodies (ABI); mitotic counts; and other clinicopathologic variables. Immunoreactivity for hTERT and TPIIalpha as well as ABI were assessed in 57 endometrial samples (12 atypical hyperplasias, 33 endometrioid carcinomas, 12 serous/clear cell carcinomas). hTERT immunoreactivity, TPIIalpha labeling indices (LI), ABI, and ratios of the indices (ABI/TPIIalpha LI) increased from atypical hyperplasias to endometrioid carcinomas to serous/clear cell carcinomas (p < 0.0001 for each variable). hTERT expression increased with ABI (p < 0.0001), TPIIalpha LI (p = 0.0019), ABI/TPIIalpha ratios (p < 0.0001), and grade (p = 0.0005), but not with FIGO stage (p = 0.2775). TPIIalpha LI, ABI, and ratios were related to high grade (p = 0.0001 for each variable), but not with FIGO stage (p = 0.7362, p = 0.7554, and p = 0.7405, respectively). TPIIalpha LI and ABI were significantly correlated in atypical hyperplasias (p = 0.0004), endometrioid carcinomas (p < 0.0001), and serous/clear cell carcinomas (p = 0.024). Immunostaining levels for hTERT were similar in atypical hyperplasias and grade 1 endometrioid carcinomas (p = 0.1956). These results suggest that hTERT expression is closely related to proliferation, apoptosis, and high grade in endometrial carcinomas, reflecting cell cycle deregulation in endometrial carcinogenesis.
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PMID:Immunohistochemical detection of human telomerase reverse transcriptase (hTERT), topoisomerase IIalpha expression, and apoptosis in endometrial adenocarcinoma and atypical hyperplasia. 1578 75

Epithelial ovarian carcinoma is thought to derive from ovarian surface epithelium (OSE). The black box of the early molecular changes in ovarian carcinogenesis is being interpreted by the development of experimental systems employing immortalised human OSE cells. However, the existing cell lines of the OSE cells have limited utility due to chromosomal instability. Our goal was to establish new immortalised human OSE cells that retain the original characteristics of the primary cells without chromosomal alterations. Using primary human OSE cells obtained from a postmenopausal patient with endometrial cancer, five cell lines ('HOSE1' lines) were newly established by infection with retroviral expression vectors containing type 16 human papillomavirus (HPV-16) E6, E7, a variant E6 (E6delta151), and Bmi1 polycomb gene, in combination with telomerase reverse transcriptase (hTERT). Consequently, five HOSE1s cell lines, HOSE1s-E6/hTERT, -E7/hTERT, -E6/E7/hTERT, -E6delta151/E7/hTERT, and -E6delta151/Bmi1/hTERT, grew beyond the population doubling number of 200. These cell lines, except for HOSE1-E6/hTERT, essentially showed the original features of the primary human OSE cells. Of them, HOSE1-E7/hTERT preserved diploidy in a kariotype analysis, and did not show transformed phenotypes in anchorage-independent growth and tumour formation. Thus, HOSE1-E7/hTERT may provide a novel model system with which to investigate the mechanisms of early molecular changes.
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PMID:Establishment of an immortalised human ovarian surface epithelial cell line without chromosomal instability. 1595 75

Several genetic mutations have been identified in human endometrial cancers, but the specific combinations of mutations required to form endometrial cancer cells remain unknown. In the present study, we established an in vitro model of endometrial carcinogenesis, in which defined genetic elements were introduced into endometrial epithelial cells to create transformed endometrial cells at different stages. Introduction of the human papillomavirus type 16 E6/E7 gene and the human telomerase reverse transcriptase (hTERT) gene into human primary endometrial epithelial cells was sufficient to generate immortalized cells. Introduction of hTERT in early passages stabilized telomeres and created immortalized cells with normal karyotype, whereas introduction of hTERT in later passages generated immortalized cells but with widespread chromosome abnormalities. However, neither of those two immortalized cell lines exhibited tumorigenic phenotypes. Tumorigenic endometrial epithelial cells with invasive capacity were created by introducing a mutant K-ras allele into immortalized cells, keeping their chromosomes intact. Inhibiting the PTEN gene and activating Akt pathways did not create tumorigenic phenotypes, although the latter conferred anchorage-independent growth capacity. These findings suggest that neoplastic transformation of human endometrial cells can occur in the absence of widespread chromosomal abnormality, and that the combination of Rb inactivation, telomerase activation and altered K-ras signaling is sufficient for in vitro neoplastic transformation. The present experimental model can help clarify the genetic requirements for endometrial carcinogenesis, and it is useful for testing and developing specific inhibitors of specific oncogenic pathways.
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PMID:Creation of tumorigenic human endometrial epithelial cells with intact chromosomes by introducing defined genetic elements. 1663 65


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