Elevated hTERT mRNA levels: A potential determinant of bronchial squamous cell carcinoma (in situ)
Corresponding Author
Peter J.F. Snijders
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Fax: +31-20-4442964
Dept. of Pathology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The NetherlandsSearch for more papers by this authorRoderick H.J. Breuer
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Department of Pulmonology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorThomas G. Sutedja
Department of Pulmonology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorMonique Egging
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorFeja J. Voorhorst
Department of Epidemiology and Biostatistics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorRenske D.M. Steenbergen
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorHans C. van der Linden
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorElle K. Risse
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorJohannes Berkhof
Department of Epidemiology and Biostatistics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorElisabeth G.E. de Vries
Department of Medical Oncology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorAte G.J. van der Zee
Department of Gynaecology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorPieter E. Postmus
Department of Pulmonology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorChris J.L.M. Meijer
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorEgbert F. Smit
Department of Pulmonology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorCorresponding Author
Peter J.F. Snijders
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Fax: +31-20-4442964
Dept. of Pathology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The NetherlandsSearch for more papers by this authorRoderick H.J. Breuer
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Department of Pulmonology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorThomas G. Sutedja
Department of Pulmonology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorMonique Egging
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorFeja J. Voorhorst
Department of Epidemiology and Biostatistics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorRenske D.M. Steenbergen
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorHans C. van der Linden
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorElle K. Risse
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorJohannes Berkhof
Department of Epidemiology and Biostatistics, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorElisabeth G.E. de Vries
Department of Medical Oncology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorAte G.J. van der Zee
Department of Gynaecology, University Hospital Groningen, Groningen, The Netherlands
Search for more papers by this authorPieter E. Postmus
Department of Pulmonology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorChris J.L.M. Meijer
Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorEgbert F. Smit
Department of Pulmonology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands
Search for more papers by this authorAbstract
Expression levels of hTERT mRNA were investigated by RT-PCR in tissue specimens of patients with (Group A) and without (Group B) clinically overt bronchial carcinoma, respectively. Bronchial carcinoma (n = 9) and distant normal (n = 9) specimens were analyzed in Group A. The chance of carcinoma seemed to increase with increasing hTERT mRNA levels (OR = 6.04, 95% CI = 1.02–37). Group B was comprised of 21 patients who underwent autofluorescence bronchoscopy. After analysis of 66 bronchial biopsies the chance of prevalent carcinoma in situ or carcinoma increased with increasing hTERT mRNA levels (OR = 6.19, 95% CI = 1.55–25). Variables like age, gender, smoking history, history of cancer within the airways or the degree of lymphocyte infiltrate in the specimens did not modify this relation. In 7 Group B patients in whom bronchial cancer was diagnosed during follow-up, biopsies taken before cancer diagnosis from both the area of the newly developed tumor and distantly from this area had been analyzed for hTERT expression. The median hTERT mRNA level in the biopsies from the area of future cancer was significantly higher than in biopsies taken from distant sites (p < 0.03). These data indicate that elevated hTERT mRNA is associated with an increased relative risk of prevalent and incident bronchial squamous cell carcinoma (in situ). © 2004 Wiley-Liss, Inc.
REFERENCES
- 1 Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999; 49: 33-64.
- 2 Venmans BJW, van Boxem TJM, Smit EF, Postmus PE, Sutedja TG. Outcome of bronchial carcinoma in situ. Chest 2000; 117: 1572–6.
- 3 Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q, Bacchetti S, Haber DA, et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 1997; 90: 785–95.
- 4 Nakayama J, Tahara H, Tahara E, Saito M, Ito K, Nakamura H, Nakanishi T, Tahara E, Ide T, Ishikawa FL. Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat Genet 1998; 18: 65–8.
- 5 Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE. Extension of life-span by introduction of telomerase into normal human cells. Science 1998; 279: 349–52.
- 6 Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A, Beijersbergen RL, Knoll JH, Meyerson M, Weinberg RA. Inhibition of telomerase limits the growth of human cancer cells. Nat Med 1999; 5: 1164–70.
- 7 Steenbergen RDM, Kramer D, Meijer CJLM, Walboomers JMM, Trott DA, Cuthbert AP, Newbold RF, Overkamp WJI, Zdzienicka MZ, Snijders PJF. Telomerase suppression by chromosome 6 in a human papillomavirus type 16-immortalized keratinocyte cell line and in a cervical cancer cell line. J Natl Cancer Inst 2001; 93: 865–72.
- 8 Hiyama K, Hiyama E, Ishioka S, Yamakido M, Inai K, Gazdar AF, Piatyszek MA, Shay JW. Telomerase activity in small cell and non-small-cell lung cancers. J Natl Cancer Inst 1996; 87: 895–902.
- 9 Albanell J, Lonardo F, Rusch V, Engelhardt M, Langenfeld J, Han W, Klimstra D, Venkatraman E, Moore MA, Dmitrovsky E. High telomerase activity in primary lung cancers: association with increased cell proliferation rates and advanced pathologic stage. J Natl Cancer Inst 1997; 89: 1609–15.
- 10 Xinarianos G, Scott FM, Liloglou T, Prime W, Callagahn J, Gosney JR, Field JK. Telomerase activity in non-small cell lung carcinomas correlates with smoking status. Int J Oncol 1999; 15: 961–5.
- 11 Hara H, Yamashita K, Shinada J, Yoshimura H, Kameya T. Clinicopathologic significance of telomerase activity and hTERT mRNA expression in non-small cell lung cancer. Lung Cancer 2001; 34: 219–26.
- 12 Kumaki F, Kawai T, Hiroi S, Shinomiya N, Ozeki Y, Ferrans VJ, Torikata C. Telomerase activity and expression of human telomerase RNA component and human telomerase reverse transcriptase in lung carcinomas. Hum Pathol 2001; 32: 188–95.
- 13 Xinarianos G, Scott FM, Liloglou T, Prime W, Turnbull L, Walshaw M, Field JK. Evaluation of telomerase activity in bronchial lavage as a potential diagnostic marker for malignant lung disease. Lung Cancer 2000; 28: 37–42.
- 14 Dikmen E, Kara M, Dikmen G, Cakmak H, Dogan P. Detection of telomerase activity in bronchial lavage as an adjunct to cytological diagnosis in lung cancer. Eur J Cardiothorac Surg 2003; 23: 194–200.
- 15 Yashima K, Litzky LA, Kaiser L, Rogers T, Lam S, Wistuba II, Milchgrub S, Srivastava S, Piatyszek MA, Shay JW, Gazdar AF. Telomerase expression in respiratory epithelium during the multistage pathogenesis of lung carcinomas. Cancer Res 1997; 57: 2373–7.
- 16
Shibuya K,
Fujisawa T,
Hoshino H,
Baba M,
Saitoh Y,
Iizasa T,
Sekine Y,
Suzuki M,
Hiroshima K,
Ohwada H.
Increased telomerase activity and elevated hTERT mRNA expression during multistage carcinogenesis of squamous cell carcinoma of the lung.
Cancer
2001;
92:
849–55.
10.1002/1097-0142(20010815)92:4<849::AID-CNCR1392>3.0.CO;2-4 CAS PubMed Web of Science® Google Scholar
- 17 Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, Chiu CP, Adams RR, Chang E, Allsopp RC, Yu J, et al. The RNA component of human telomerase. Science 1995; 269: 1236–41.
- 18 Marchetti A, Bertacca G, Buttitta F, Chella A, Quattrocolo G, Angeletti CA, Bevilacqua G. Telomerase activity as a prognostic indicator in stage I non-small cell lung cancer. Clin Cancer Res 1999; 5: 2077–81.
- 19 Wang L, Soria JC, Kemp BL, Liu DD, Mao L, Khuri FR. hTERT expression is a prognostic factor of survival in patients with stage I non-small cell lung cancer. Clin Cancer Res 2002; 8: 2883–9.
- 20 Broccoli D, Young JW, de Lange T. Telomerase activity in normal and malignant hematopoietic cells. Proc Natl Acad Sci USA 1995; 92: 9082–6.
- 21 Counter CM, Gupta J, Harley CB, Leber B, Bacchetti S. Telomerase activity in normal leukocytes and in hematological malignancies. Blood 1995; 85: 2315–20.
- 22 Hooijberg E, Ruizendaal JJ, Snijders PJF, Kueter EWM, Walboomers JMM, Spits H. Immortalization of human CD8+ T cell clones by ectopic expression of telomerase reverse transcriptase. J Immunol 2000; 165: 4239–45.
- 23 Venmans BJ, Smit EF, Postmus PE, Sutedja TG. Autofluorescence bronchoscopy in the detection of squamous metaplasia and dysplasia in current and former smokers. J Natl Cancer Inst 1999; 91: 562–3.
- 24 Snijders PJF, van Duin M, Walboomers JMM, Steenbergen RDM, Risse EK, Helmerhorst TJ, Verheijen RHM, Meijer CJLM. Telomerase activity exclusively in cervical carcinomas and a subset of cervical intraepithelial neoplasia grade III lesions: strong association with elevated messenger RNA levels of its catalytic subunit and high-risk human papillomavirus DNA. Cancer Res 1998; 58: 3812–18.
- 25 Goldstein H. Multilevel statistical models, 2nd ed. London: Edward Arnold, 1995.
- 26 Arinaga M, Shimizu S, Gotoh K, Haruki N, Takahashi T, Takahashi T, Mitsudomi T. Expression of human telomerase subunit genes in primary lung cancer and its clinical significance. Ann Thorac Surg 2000; 70: 401–5.
- 27 Wick M, Zubov D, Hagen G. Genomic organization and promoter characterization of the gene encoding the human telomerase reverse transcriptase (hTERT). Gene 1999; 232: 97–106.
- 28 Kilian A, Bowtell DD, Abud HE, Hime GR, Venter DJ, Keese PK, Duncan EL, Reddel RR, Jefferson RA. Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types. Hum Mol Genet 1997; 6: 2011–9.
- 29
Ulaner GA,
Hu JF,
VU TH,
Oruganti H,
Giudice LC,
Hoffman AR.
Regulation of telomerase by alternate splicing of human telomerase reverse transcriptase (hTERT) in normal and neoplastic ovary, endometrium and myometrium.
Int J Cancer
2000;
85:
330–5.
10.1002/(SICI)1097-0215(20000201)85:3<330::AID-IJC6>3.0.CO;2-U CAS PubMed Web of Science® Google Scholar
- 30 Krams M, Claviez A, Heidorn K, Krupp G, Parwaresch R, Harms D, Rudolph P. Regulation of telomerase activity by alternate splicing of human telomerase reverse transcriptase mRNA in a subset of neuroblastomas. Am J Pathol 2001; 159: 1925–32.
- 31 Soria JC, Xu X, Liu DD, Lee JJ, Kurie J, Morice RC, Khuri F, Mao L, Hong WK, Lotan R. Retinoic acid receptor beta and telomerase catalytic subunit expression in bronchial epithelium of heavy smokers. J Natl Cancer Inst 2003; 95: 165–8.
Citing Literature
