| Autor: |
Steenbergen, Renske D.M., Kramer, Debbie, Meijer, Chris J.L., Walboomers, Jan M.M., Trott, Deborah A., Cuthbert, Andrew P., Newbold, Robert F., Overkamp, Wilhelmina J.I., Zdzienicka, Malgorzata Z., Snijders, Peter J.F., Steenbergen, R D, Kramer, D, Meijer, C J, Walboomers, J M, Trott, D A, Cuthbert, A P, Newbold, R F, Overkamp, W J, Zdzienicka, M Z, Snijders, P J |
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| Zdroj: |
JNCI: Journal of the National Cancer Institute; 6/6/2001, Vol. 93 Issue 11, p865-872, 8p, 9 Diagrams, 1 Chart |
| Abstrakt: |
Background: High-risk human papillomavirus (HPV) types play a major role in the development of cervical cancer in vivo and can induce immortalization of primary human keratinocytes in vitro. Activation of the telomere-lengthening enzyme telomerase constitutes a key event in both processes. Because losses of alleles from chromosome 6 and increased telomerase activity have been observed in high-grade premalignant cervical lesions, we analyzed whether human chromosome 6 harbors a putative telomerase repressor locus that may be involved in HPV-mediated immortalization.Methods: Microcell-mediated chromosome transfer was used to introduce chromosomes 6 and 11 to the in vitro generated HPV type 16 (HPV16)-immortalized keratinocyte cell line FK16A and to the in vivo derived HPV16-containing cervical cancer cell line SIHA: Hybrid clones were analyzed for growth characteristics, telomerase activity, human telomerase reverse transcriptase (hTERT) and HPV16 E6 expression, and telomere length. FK16A hybrid clones were also transduced with an hTERT-containing retrovirus to examine the effect of ectopic hTERT expression on growth. Statistical tests were two-sided.Results: Introduction of human chromosome 6 but not of chromosome 11 to both cell lines yielded hybrid cells that demonstrated crisis-like features (i.e., enlarged and flattened morphology, vacuolation, and multinucleation) and underwent growth arrest after a marked lag period. In the chromosome 6 hybrid clones analyzed, telomerase activity and hTERT messenger RNA (mRNA) expression were statistically significantly reduced compared with those in the chromosome 11 hybrid clones (for telomerase activity, P =.004 for the FK16A hybrids and P =.039 for the SiHa hybrids; for hTERT mRNA expression, P =.003 for the FK16A hybrids). The observed growth arrest was associated with telomeric shortening. Ectopic expression of hTERT in FK16A cells could prevent the telomeric shortening-based growth arrest induced by chromosome 6.Conclusions: Chromosome 6 may harbor a repressor of hTERT transcription, the loss of which may be involved in HPV-mediated immortalization. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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