Journal of Pathology and Translational Medicine

Original Articles

Telomerase Activity in Urethane-Induced Mouse Lung Tumorigenesis.: Ji Sun Song, Soon Hee Jung, Sang Yeop Yi, Hwa Eun Oh, Mee Yon Cho, Kwang Hwa Park; Korean J Pathol. 2011;45(3):261-270.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.3.261

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BACKGROUND
Telomerase activity in precancerous conditions of lung adenocarcinomas has not been well studied. This study is designed to investigate the role of telomerase in premalignant lesions of urethane-induced mouse lung adenocarcinoma.
METHODS
We harvested A/J mouse lung tissues at 3, 6, 9, 12, 28, 41, and 48 weeks after intraperitoneal urethane treatment, and classified each lesion in terms of histologic findings. We examined telomerase activity using a modified version of the telomeric repeat amplification protocol assay using both gel-based and enzyme linked immunosorbent assay methods. An immunohistochemical analysis of proliferating cell nuclear antigen (PCNA) was performed.
RESULTS
In urethane-induced mouse lung tissues, it was sequentially developed from hyperplasia, adenoma, and eventually to adenocarcinoma. Telomerase activity began to show a positive level in tissues with no histologically visible nodule after urethane administration. It revealed a statistically significant increase in hyperplasia compared to the "control" lung tissue (p<0.05), which was proportionally elevated relative to adenoma and adenocarcinoma. There was a direct correlation between telomerase activity and the PCNA labeling index (p<0.05).
CONCLUSIONS
The elevation of telomerase activity in normal-appearing lung lesions is thought to be a possible marker of early detection of pulmonary adenocarcinoma.

Citations

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Non-invasive quantification of cell-free DNA mutations in plasma during lung tumor progression in mice
Soo-Jin Kim, Eunhee Kim, Kyung-Taek Rim
Cancer Biomarkers.2017; 20(4): 477. CrossRef

Telomerase Activity and Expression of Telomerase RNA in Malignant Fibrous Histiocytoma.: Jinyoung Yoo, Seok Jin Kang, Bung Kee Kim; Korean J Pathol. 2000;34(8):581-587.

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Abstract PDF: Telomerase is an RNA-dependent DNA polymerase that synthesizes TTAGGG telomeric DNA onto chromosomal ends to compensate for sequence loss during replication. It has been detected in a variety of human malignancies, suggesting that such activity may play a role in the tumorigenic process. To determine whether telomerase is reactivated in malignant fibrous histiocytoma, 12 tissue samples with this tumor were analyzed for the telomerase activity by a radioactive PCR-based TRAP (telomeric repeat amplification protocol) assay. All of the tumors were further investigated for the expression of human telomerase RNA (hTR) by an in situ hybridization (ISH). Telomerase activity was detected in one (8.3%) sample. Expression of hTR was demonstrated in 7 (58.3%): one telomerase-positive and six telomerase-negatives. These data indicate that the reactivation of telomerase is an uncommon event and not an important factor involved in tumorigenesis in malignant fibrous histiocytoma. It is noteworthy that 50% of the patients with grade 2 tumors expressed hTR, suggesting that telomerase RNA may be useful as a marker for identifying tumor aggressiveness earlier than the conventional histopathologic grading scale.

Telomerase Activity and Expression of MIB-1 and bcl-2 in Human Chorionic Villi from Early and Term Normal Pregnancy.: Jung Sook Cho, Young Soon Kang, In Gul Moon, Bum Chae Choi, Jong Pyo Lee, Hoon Taek Lee, Sung Ran Hong; Korean J Pathol. 2000;34(11):927-933.

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Abstract PDF: Telomerase is an enzyme that maintains telomeres and prevents telomere shortening, and may be linked with cellular proliferation or the aging process. The purpose was to examine telomerase activity in human chorionic villi from early and term normal pregnancies, and to analyze the correlation of telomerase activity (TA) with MIB-1 & bcl-2. A total of 37 placentae were obtained from 16 early and 21 term pregnancies. TA was assayed by telomeric repeat amplification protocol, and immunohistochemical staining was performed for MIB-1 & bcl-2 expression. TA & MIB-1 expression were strong in early placenta, but bcl-2 was highly expressed in term placentae. Thirteen (81.25%) of 16 early placentae showed TA, but only 2 (9.52%) of 21 term placentae expressed TA (p<0.01). MIB-1 was observed in nuclei of cytotrophoblast, and the expression rate was 16.09% in early placentae and 2.87% in term placentae (p<0.01). bcl-2 was observed only in the cytoplasm of syncytiotrophoblast. Term placenta demonstrated stronger expression of bcl-2 compared to early placentae (p<0.05). These findings suggest that TA, MIB-1 & bcl-2 expression are critically regulated over the course of gestation: cytotrophoblast, main cells of early chorionic villi, may be a common source of telomerase and proliferative activity. The TA showed good correlation with cellular proliferative activity. Syncytiotrophoblast, may be a main source of bcl-2 expression which is stronger in the term placentae.

Telomerase mRNA Expression by In Situ Hybridization in Premalignant Lesions and Carcinomas of the Breast.: Young Kyung Bae, Dong Sug Kim, Soo Jung Lee, Koing Bo Kwun; Korean J Pathol. 2001;35(1):53-59.

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Abstract PDF: BACKGROUND
Telomerase is a ribonucleoprotein, DNA polymerase that synthesizes telomere repeats onto chromosomal ends and maintains telomere length. Telomerase activity has been detected in a broad range of human malignant neoplasms, but not in normal somatic cells. So, activation of telomerase may represent an essential step in the malignant transformation of cells. However, the expression of telomerase in premalignant lesions remains relatively unexplored. This study was conducted to investigate the reactivation of telomerase in the carcinogenesis of human breast tissue.
METHODS
In situ hybridization for the telomerase RNA component (human telomerase mRNA; hTR) was used in a normal breast tissue (n=41), florid ductal hyperplasia (FDH) (n=10), atypical ductal hyperplasia (ADH) (n=3), ductal carcinoma in situ (DCIS) (n=44) and invasive carcinoma (n=33). hTR expression in relation to p53 status and the pathologic parameters in breast cancer was also studied.
RESULTS
Expression of hTR was demonstrated in 13 samples (31.7%) of normal breast tissues, 4 (40%) of FDH, 3 (100%) of ADH, 42 (95.5%) of DCIS, and 33 (100%) of invasive carcinoma. The rate of hTR expression of ADH was significantly different from that of FDH (p<0.05), and there were no differences in hTR expression rates among ADH, DCIS and invasive carcinomas. There was no correlation between hTR expression and nuclear grade, tumor size, and p53 status in invasive carcinomas.
CONCLUSION
These results suggest that telomerase activation may be an early event and an essential step in the carcinogenesis of human breast tissue, and that telomerase has no correlations with p53 status and prognostic parameters.

In Situ Detection of mRNA and RNA Component of Human Telomerase in Proliferative Lesions of the Stomach.: Mi Sook Kim, Sang Woo Juhng; Korean J Pathol. 2001;35(4):299-305.

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Abstract PDF: BACKGROUND
Proliferative lesions of the stomach were investigated by in situ hybridization using RNA probes for telomerase components and compared with the results by TRAP (telomeric repeat amplification protocol) assay.
METHODS
RNA probes for hTR (human telomerase RNA component) and hTERT (mRNA coding for a catalytic subunit of human telomerase) were made by cloning and in vitro transcription. The probes were applied for in situ hybridization in 23 cases of adenocarcinoma of the intestinal type and adjacent dysplasia, and in the normal and metaplastic mucosa of the stomach.
RESULTS
Telomerase activity by TRAP was positive in all cases of adenocarcinoma, most cases of dysplasia, and many cases of normal mucosa. hTR in situ hybridization showed positive staining in the adenocarcinoma cells, dysplastic cells, a few cells in the proliferation zone of the normal mucosa, and a few infiltrated lymphocytes. hTERT showed positive staining in the same cells.
CONCLUSIONS
Telomerase is expressed in most cases of dysplastic lesions and is thought to be acquired in the early steps of carcinogenesis. The expression is noted in a few cells of the normal proliferative zones and the infiltrated lymphocytes, emphasizing the importance of in situ detection of telomerase at the cell level.

The Expression of Telomerase Reverse Transcriptase Protein is an Independent Prognostic Marker in Early Stage Non-Small Cell Lung Carcinomas.: Ji Han Jung, Chan Kwon Jung, Ahwon Lee, Gyeongsin Park, Jinyoung Yoo, Kyo Young Lee; Korean J Pathol. 2007;41(2):95-102.

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Abstract PDF: BACKGROUND
The catalytic subunit of telomerase, hTERT (telomerase reverse transcriptase), is one of the most important components of telomerase, and performs a pivotal role in the mechanism underlying the regulation of telomerase activity in cellular immortalization and carcinogenesis. The principal objective of this study was to investigate hTERT expression in patients with non-small cell lung carcinomas (NSCLCs), and to evaluate its clinical significance and association with the expression of p16 and p53.
METHODS
Using tissue microarray, the protein expression profiles of hTERT, p16 and p53 were investigated via immunohistochemistry in 167 samples of NSCLCs.
RESULTS
Expression was observed in 54.5% (91/167) of the tumors, which were predominantly squamous cell carcinomas. Patients evidencing hTERT expression in their tumors exhibited significantly poorer survival rates than did patients without hTERT expression in early-stage NSCLCs (p=0.0125). According to the results of our Cox regression analysis, hTERT expression proved to be an independent prognostic factor (p=0.006), particularly for squamous cell carcinomas (p=0.019). hTERT expression was not correlated with p16 expression, but was rather associated with the expression of p53 (p=0.002).
CONCLUSIONS
Our results show that hTERT may perform a function in the progression of NSCLC, and that its detection may be useful in predicting the prognosis of NSCLC patients in the early stages of the disease, as well as in the development of a targeted therapy in these tumors.

Telomerase activity and Expression of MIB-1, Fas and Fas Ligand in Placentas from Women with and without Intrauterine Growth Retardation.: Yi Kyeong Chun, Sung Ran Hong, Moon Ho Yang; Korean J Pathol. 2005;39(1):34-40.

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Abstract PDF: BACKGROUND
The placenta from a pregnancy that is complicated by intrauterine growth retardation (IUGR) tends to be smaller than that from a normal pregnancy. To investigate this difference, we analyzed the telomerase activity, the proliferative activity and the mRNA levels of apoptosis mediators in placentas.
METHODS
In 20 placentas from normal third-trimester pregnancies and 22 placentas form pregnancies that were complicated by IUGR, the telomerase activity was detected by a telomeric repeat amplification protocol assay. The proliferative activity was assessed by immunohistochemical staining using the MIB-1 monoclonal antibody. The expression of the apoptosis mediator was evaluated by semi-quantitative reverse transcription-polymerase chain reactions for fas and fas ligand.
RESULTS
Telomerase activity was detected in 2 (10%) of 20 normal placentas, whereas it was not observed in all tested 13 placentas that were associated with IUGR. The proliferative activity was significantly low in the placentas that were associated with IUGR (7.44+/-2.96%), compared with the normal placentas (11.0+/-3.48%, p=0.002). There was no statistically significant difference in the mRNA levels of fas or fas ligand between two groups.
CONCLUSIONS
Low telomerase and proliferative activities in the placenta may play a role in the pathogenesis of IUGR.

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