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Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix

Oncogene volume 23, pages 7441–7447 (2004)Cite this article

Abstract

Although human papillomavirus (HPV) has been defined as the pathogen for cervical carcinomas, molecular events underlying the oncogenic process are unclear. As telomere dysfunction-mediated chromosomal instability and telomerase activation have been suggested as key events in carcinogenesis, we dissected the dynamic changes in telomere length, checkpoint response, and temporal profile of telomerase expression during the evolution from precursor lesions (cervical intraepithelial neoplasia, CINs) to invasive cancers of the uterine cervix in sequential samples from 16 patients. Telomeres were significantly shortened in all CIN samples and no further substantial attritions occurred in most cases with the acquisition of malignant phenotype. Very short telomeres were coupled with constitutive activation of the DNA damage response pathway (Chk2 phosphorylation) and increased cellular proliferation in those cervical specimens. Telomerase reverse transcriptase (hTERT) expression was preferably induced at advanced CINs or invasive cancers. The present finding demonstrates that excessive telomere shortening predominantly occurs in the early carcinogenesis of the uterine cervix largely prior to telomerase activation. Widespread over-erosion of telomeres or telomere dysfunction in very early stages of cervical tumorigenesis might fuel transformation processes by driving chromosomal instability.

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References

  • Anderson S, Shera K, Ihle J, Billman L, Goff B, Greer B, Tamimi H, McDougall J and Klingelhutz A . (1997). Am. J. Pathol., 151, 25–31.

  • Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L and DePinho RA . (2000). Nature, 406, 641–645.

  • Aubele M, Zitzelsberger H, Schenck U, Walch A, Hofler H and Werner M . (1998). Cancer, 84, 375–379.

  • Burd EM . (2003). Clin. Microbiol. Rev., 16, 1–17.

  • Chang S, Khoo C and DePinho RA . (2001). Semin. Cancer Biol., 11, 227–239.

  • Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB and Bacchetti S . (1992). EMBO J., 11, 1921–1929.

  • Der-Sarkissian H, Bacchetti S, Cazes L and Londono-Vallejo JA . (2004). Oncogene, 23, 1221–1228.

  • DiTullio Jr RA, Mochan TA, Venere M, Bartkova J, Sehested M, Bartek J and Halazonetis TD . (2002). Nat. Cell Biol., 4, 998–1002.

  • Evans MF, Koreth J, Bakkenist CJ, Herrington CS and McGee JO . (1998). Oncogene, 16, 2557–2564.

  • Fagagna Fd F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, Saretzki G, Carter NP and Jackson SP . (2003). Nature, 426, 194–198.

  • Fehrmann F and Laimins LA . (2003). Oncogene, 22, 5201–5207.

  • Ferber MJ, Montoya DP, Yu C, Aderca I, McGee A, Thorland EC, Nagorney DM, Gostout BS, Burgart LJ, Boix L, Bruix J, McMahon BJ, Cheung TH, Chung TK, Wong YF, Smith DI and Roberts LR . (2003). Oncogene, 22, 3813–3820.

  • Giannoudis A, Evans MF, Southern SA and Herrington CS . (2000). Br. J. Cancer, 82, 424–428.

  • Hackett JA and Greider CW . (2002). Oncogene, 21, 619–626.

  • Hahn WC . (2003). J. Clin. Oncol., 21, 2034–2043.

  • Heselmeyer-Haddad K, Janz V, Castle PE, Chaudhri N, White N, Wilber K, Morrison LE, Auer G, Burroughs FH, Sherman ME and Ried T . (2003). Am. J. Pathol., 163, 1405–1416.

  • Jarboe EA, Liaw KL, Thompson LC, Heinz DE, Baker PL, McGregor JA, Dunn T, Woods JE and Shroyer KR . (2002). Oncogene, 21, 664–673.

  • Karlseder J, Broccoli D, Dai Y, Hardy S and de Lange T . (1999). Science, 283, 1321–1325.

  • Klingelhutz AJ, Foster SA and McDougall JK . (1996). Nature, 380, 79–82.

  • Kyo S, Takakura M, Ishikawa H, Sasagawa T, Satake S, Tateno M and Inoue M . (1997). Cancer Res., 57, 1863–1867.

  • Lengauer C, Kinzler KW and Vogelstein B . (1998). Nature, 396, 643–649.

  • McMurray HR and McCance DJ . (2003). J. Virol., 77, 9852–9861.

  • Meeker AK, Hicks JL, Platz EA, March GE, Bennett CJ, Delannoy MJ and De Marzo AM . (2002). Cancer Res., 62, 6405–6409.

  • Oh H, Wang SC, Prahash A, Sano M, Moravec CS, Taffet GE, Michael LH, Youker KA, Entman ML and Schneider MD . (2003). Proc. Natl. Acad. Sci. USA, 100, 5378–5383.

  • O'Hagan RC, Chang S, Maser RS, Mohan R, Artandi SE, Chin L and DePinho RA . (2002). Cancer Cell, 2, 149–155.

  • Pandita TK . (2002). Oncogene, 21, 611–618.

  • Pihan GA, Wallace J, Zhou Y and Doxsey SJ . (2003). Cancer Res., 63, 1398–1404.

  • Rudolph KL, Millard M, Bosenberg MW and DePinho RA . (2001). Nat. Genet., 28, 155–159.

  • Shay JW, Zou Y, Hiyama E and Wright WE . (2001). Hum. Mol. Genet., 10, 677–685.

  • Snijders PJ, van Duin M, Walboomers JM, Steenbergen RD, Risse EK, Helmerhorst TJ, Verheijen RH and Meijer CJ . (1998). Cancer Res., 58, 3812–3818.

  • Southern SA, Evans MF and Herrington CS . (1997). Cancer Res., 57, 4210–4213.

  • Takakura M, Kyo S, Kanaya T, Tanaka M and Inoue M . (1998). Cancer Res., 58, 1558–1561.

  • Umayahara K, Numa F, Suehiro Y, Sakata A, Nawata S, Ogata H, Suminami Y, Sakamoto M, Sasaki K and Kato H . (2002). Genes Chromosomes Cancer, 33, 98–102.

  • van Heek NT, Meeker AK, Kern SE, Yeo CJ, Lillemoe KD, Cameron JL, Offerhaus GJ, Hicks JL, Wilentz RE, Goggins MG, De Marzo AM, Hruban RH and Maitra A . (2002). Am. J. Pathol., 161, 1541–1547.

  • Veldman T, Horikawa I, Barrett JC and Schlegel R . (2001). J. Virol., 75, 4467–4472.

  • Vukovic B, Park PC, Al-Maghrabi J, Beheshti B, Sweet J, Evans A, Trachtenberg J and Squire J . (2003). Oncogene, 22, 1978–1987.

  • Zhang A, Zheng C, Hou M, Lindvall C, Li K-J, Erlandsson F, Bjorkholm M, Gruber A, Blennow E and Xu D . (2003). Am. J. Hum. Genet., 72, 940–948.

  • Zhang A, Zheng C, Hou M, Lindvall C, Wallin KL, Angstrom T, Yang X, Hellstrom AC, Blennow E, Bjorkholm M, Zetterberg A, Gruber A and Xu D . (2002). Genes Chromosomes Cancer, 34, 269–275.

  • Zhang A, Zheng C, Lindvall C, Hou M, Ekedahl J, Lewensohn R, Yan Z, Yang X, Henriksson M, Blennow E, Nordenskjold M, Zetterberg A, Bjorkholm M, Gruber A and Xu D . (2000). Cancer Res., 60, 6230–6235.

  • zur Hausen H . (2002). Nat. Rev. Cancer, 2, 342–350.

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Acknowledgements

We thank S Bug and J Yang (Texas University at Austin, USA) for technical assistance. This work was supported by research grants from the Swedish Cancer Society, the Swedish Research Council, Stockholm County Council, the Cancer Society in Stockholm, Karolinska Institute, and Swedish Society of Medicine. K-LW and DX were research fellows of the Swedish Research Council.

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  1. Contributed equally to this work

Authors and Affiliations

  1. Department of Molecular Medicine, Karolinska Institute, Karolinska University Hospital, CMM, Stockholm, SE-171 76, Sweden

    Anju Zhang, Jianliu Wang, Biying Zheng, Xidan Li, Magnus Nordenskjörd & Keng-Ling Wallin

  2. Department of Urology, Karolinska Institute, Karolinska University Hospital, Stockholm, SE-171 76, Sweden

    Xiaolei Fang

  3. Cytology Laboratory, Umeå University Hospital, Umeå, SE-901 87, Sweden

    Tord Ångström

  4. Department of Medicine, Division of Hematology, Karolinska Institute, Karolinska University Hospital, Stockholm, SE-171 76, Sweden

    Cheng Liu, Magnus Björkholm, Astrid Gruber & Dawei Xu

  5. Department of Oncology and Pathology, Karolinska Institute, Karolinska University Hospital, Stockholm, SE-171 76, Sweden

    Anju Zhang & Fredrik Erlandsson

  6. Department of Gynecology, Peking University, People's Hospital, Beijing, 100083, People's Republic of China

    Jianliu Wang

  7. Department of Urology, Qilu Hospital, Shandong University, Jinan, 250108, People's Republic of China

    Xiaolei Fang

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Correspondence to Keng-Ling Wallin or Dawei Xu.

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Zhang, A., Wang, J., Zheng, B. et al. Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix. Oncogene 23, 7441–7447 (2004). https://doi.org/10.1038/sj.onc.1207527

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