Telomerase activity and expression of the telomerase catalytic subunit gene in non-small cell lung cancer: correlation with decreased apoptosis and clinical prognosis.
OBJECTIVE
To investigate the level of telomerase activation (TA) and telomerase catalytic subunit (hEST2) gene mRNA in patients with non-small cell lung cancer, and determine whether they are associated with tumor cell apoptosis, stage, and clinical outcome.


METHODS
Primary tumor specimens from 58 patients untreated with chemotherapy and 10 cases of histologically benign and adjacent lung tissue were analyzed. TA and hEST2 were measured by means of a modified telomerase repeat amplification protocol (TRAP) assay and in situ hybridization (ISH), respectively. Terminal deoxynucleotidyl transferase (TdT)-mediated biotin dUTP nick end-labeling (TUNEL) was used to evaluate apoptotic cells. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect bcl-2 mRNA expression.


RESULTS
TA and hEST2 were detected in 45 (77.6%) and 43 (74.1%) of 58 tumor specimens, respectively, and not detected in specimens of adjacent and benign lung tissue. One case expressed hEST2 as a weak positive. Statistically significant positive association was found between the level of TA and hEST2 (r = 0.85, P = 0.001). TA and hEST2 were associated with tumor stage, but not associated with tumor grade, gender and patient age. Positive rate of bcl-2 mRNA was 38 (65.5%) of 58 tumor specimens. The mean apoptotic index in the bcl-2 positive group (9.5 +/- 1.3) was lower than that in the bcl-2 negative one (19.8 +/- 2.1, P < 0.05), suggesting that apoptotic index may be inversely associated with bcl-2 expression (r = -0.48, P = 0.041). Bcl-2 expression in the TA and hEST2 positive group (92.1% and 89.4%) was higher than that in the negative one (50.0% and 45.0%, P = 0.043 and P = 0.032, respectively). The apoptotic index was lower in the TA or hEST2 positive group (8.2 +/- 1.4, 10.7 +/- 1.1) than in the negative one (20.5 +/- 1.6, 24.2 +/- 2.1, P < 0.05). A statistically significant inverse association was found between TA or hEST2 and apoptotic index (r = -0.45, P = 0.02 and r = -0.51, P = 0.001, respectively). Positive correlation was also detected between TA or hEST2 and bcl-2 expression (r = 0.86, P = 0.01 and r = 0.73, P = 0.024, respectively). The level of hEST2 mRNA and apoptotic index were associated with clinical outcome in a multivariate cox regression analysis.


CONCLUSIONS
High TA and hEST2 were frequently detected in primary non-small cell lung cancer untreated with chemotherapy, having high bcl-2 expression and a low tumor cell apoptotic rate. This suggests that both TA and hEST2 are correlated with the deregulation of apoptosis. hEST2 and apoptotic index have prognostic significance in patients with non-small cell lung cancer.
Wang
J
J
Department of Internal Medicine, School of Oncology, Beijing University, Beijing 100036, China. Wangjie_CC@yahoo.com
Liu
X
X
Jiang
W
W
Liang
L
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*
D004268:DNA-Binding Proteins; C509186:TERT protein, human; D019098:Telomerase