20q gain associates with immortalization: 20q13.2 amplification correlates with genome instability in human papillomavirus 16 E7 transformed human uroepithelial cells

Savelieva, Elena; Belair, Cassandra D.; Newton, Michael A.; DeVries, Sandy; Gray, Joe W.; Waldman, Frederic M.; Reznikoff, Catherine A.

doi:10.1038/sj.onc.1200868

Cited by 125 publications

(107 citation statements)

References 24 publications

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“…Transduction at early PD (before the putative proliferation barriers) ensures that the immortal cell line remains diploid, whereas transduction at a later stage leads to aneuploidy (O'Hare et al, 2001). In agreement, TERT-NHUC had normal karyotypes, with the exception of one cell line which contained a subclone with gain of material on chromosome 20q, an aberration previously associated with immortalisation of NHUC (Savelieva et al, 1997). As expected, TERT-NHUC were not tumorigenic.…”

Section: Discussionsupporting

confidence: 76%

Expression of hTERT immortalises normal human urothelial cells without inactivation of the p16/Rb pathway

et al. 2006

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The CDKN2A locus is frequently inactivated in urothelial cell carcinoma (UCC), yet how this alteration contributes to bladder tumorigenesis is not known. Although most UCC express telomerase, inactivation of the p16/Rb pathway is generally required for in vitro immortalisation. This and the involvement of p16 in senescence of normal human urothelial cells (NHUC) suggest that CDKN2A deletion may aid bypass of senescence and allow immortalisation. CDKN2A encodes p16 and p14 ARF and therefore inactivation of this locus can disrupt both the Rb and p53 tumour suppressor pathways. Retrovirusmediated transduction was used to specifically modulate the p16/Rb and/or p53 tumour suppressor pathways in NHUC and to express human telomerase reverse transcriptase (hTERT). Expression of hTERT bypassed Rb and p53 pathway-dependent barriers to proliferation and immortalised NHUC. TERT-NHUC had normal karyotypes, were non-tumorigenic and unexpectedly retained CDKN2A. Thus, the phenotypic significance of inactivation of CDKN2A in UCC may not be solely related to bypass of senescence. Phenotypic assays in human urothelial cells have relied on cell strains derived from invasive tumours or NHUC immortalised by expression of SV40-large T. The production of genetically normal but immortal NHUC lines now provides a valuable platform for experiments to examine the timing and combination of events necessary for UCC tumorigenesis.

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Section: Discussionsupporting

confidence: 76%

Expression of hTERT immortalises normal human urothelial cells without inactivation of the p16/Rb pathway

et al. 2006

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“…There is also a strong association between 20q13.2 ampli®cation and genomic instability in HPVtransformed uroepithelial cells and between high frequency of 20q gain and cell immortalization (Savelieva et al, 1997;Yeager et al, 1998). Indeed, 20q gain is thought to re¯ect one genetic alteration required by tumor cells to overcome senescence (Savelieva et al, 1997;Yeager et al, 1998). Lastly, we have documented that expression of CIR1/CROC1 is up-regulated early in cell immortalization and is common in tumor-derived cell lines.…”

Section: Expression Of Cir1/croc1 In Human Tissues and Tumor-derived mentioning

confidence: 66%

“…breast cancer, where it correlates with aggressiveness and poor prognosis (Tanner et al, 1995). There is also a strong association between 20q13.2 ampli®cation and genomic instability in HPVtransformed uroepithelial cells and between high frequency of 20q gain and cell immortalization (Savelieva et al, 1997;Yeager et al, 1998). Indeed, 20q gain is thought to re¯ect one genetic alteration required by tumor cells to overcome senescence (Savelieva et al, 1997;Yeager et al, 1998).…”

Section: Expression Of Cir1/croc1 In Human Tissues and Tumor-derived mentioning

confidence: 99%

Up-regulation of CIR1/CROC1 expression upon cell immortalization and in tumor-derived human cell lines

Broomfield

Lavery

et al. 1998

Oncogene

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Acquisition of the immortal phenotype by tumor cells represents an essential and potentially rate-limiting step in tumorigenesis. To identify changes in gene expression that are associated with the early stages of cell immortalization, we compared genetically matched pairs of pre-immortal and immortal human cell clones by mRNA di erential display. Two transcripts, denoted CIR1 and CIR2, were identi®ed which were up-regulated in immortal cells. Sequence analysis revealed CIR1 to be identical to the recently cloned CROC1/UEV-1 gene, whereas CIR2 corresponds to an as yet uncharacterized 1.2 kb mRNA. A 5 ± 6-fold elevation in CIR1/CROC1 expression and a 2 ± 3-fold elevation in CIR2 expression were observed in SV40-transformed human enbryonic kidney cells immediately following proliferative crisis, suggesting a potential role for these genes in immortalization. Expression of CIR1/CROC1 was found to be elevated also in a variety of immortal human tumorderived cell lines, as compared to their normal tissue counterparts. These results are compatible with induction of CIR1/CROC1 being an early event in the acquisition of immortality and with a role for this gene in the immortal phenotype of tumor cells.

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“…20 The GATA-3 gene is located at 10p15, a region, which is more than incidentally altered in HPV-immortalized cells and in cervical carcinomas. 4,[21][22][23][24][25][26] In addition, putative senescence and telomerase repressor loci have recently been identified at 10p14-p15 and 10p15, respectively. 27,28 Therefore, further functional studies are warranted to find out whether GATA-3 deregulation is involved in HPV-mediated immortalization and cervical carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Down-Regulation of GATA-3 Expression during Human Papillomavirus-Mediated Immortalization and Cervical Carcinogenesis

Steenbergen

OudeEngberink

Kramer

et al. 2002

The American Journal of Pathology

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To identify cellular genes that may be involved in human papillomavirus (HPV)-mediated immortalization mRNA differential display analysis was performed on preimmortal and subsequent immortal stages of four human keratinocyte cell lines transformed by HPV type 16 or 18 DNA. This yielded a cDNA fragment encoding the transcription factor GATA-3 that was strongly reduced in intensity in all immortal stages of the four cell lines. A marked reduction in both GATA-3 mRNA and protein expression in HPV-immortalized cell lines was confirmed by reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunohistochemistry and was also shown to be apparent in cervical carcinoma cell lines. Immunohistochemical analysis of cervical tissue specimens showed a clear nuclear staining for GATA-3 in normal cervical squamous epithelium (n ‫؍‬ 14) and all cervical intraepithelial neoplasia (CIN) I (n ‫؍‬ 6) and CIN II lesions (n ‫؍‬ 2). In contrast, 11% (1 of 9) of CIN III lesions and 67% (8 of 12) of cervical squamous cell carcinomas revealed a complete absence of GATA-3 immunostaining. Hence, complete down-regulation of GATA-3 expression represents a rather late event during cervical carcinogenesis. Whether GATA-3 down-regulation is etiologically involved in HPV-mediated immortalization and cervical carcinogenesis remains to be examined. Infection with high-risk human papillomavirus (HPV) types is the most significant risk factor for the development of cervical cancer and HPV DNA can be detected in almost all cervical squamous cell carcinomas. 1 HPV functions are, however, not sufficient for the development of cervical cancer and additive oncogenic events involving host cell genes are required, consistent with a multistep process of carcinogenesis. To gain better insight in HPV-mediated carcinogenesis in vitro model systems have been proven very valuable. High-risk HPV types, in particular HPV 16 and HPV 18, can induce immortalization of primary human epithelial cells in vitro. [2][3][4] Studies involving somatic cell fusions and microcell-mediated chromosome transfers have indicated that particularly recessive gene alterations are crucial for immortalization of HPV-containing epithelial cells. 5,6 HPV-mediated immortalization is associated with an arrest of telomeric shortening and activation of the telomere lengthening enzyme telomerase. 4,7 Moreover, activation of telomerase, by up-regulation of its catalytic subunit human telomerase reverse transcriptase gene, seemed to be necessary and sufficient for immortalization of HPV-transfected keratinocytes. 6,8,9 In addition, expression of the viral oncogene HPV 16 E6 from a heterologous promoter has been shown to activate telomerase in primary keratinocytes. 10 However, expression of HPV 16 and HPV 18 E6 from their native promoter in the context of the fulllength virus genome did not result in telomerase activation, 4 indicating that additive events are required.Recent studies have shown that yet unknown genes residing at chromosomes 3, 4, and 6 can regulate telomer...

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20q gain associates with immortalization: 20q13.2 amplification correlates with genome instability in human papillomavirus 16 E7 transformed human uroepithelial cells

Cited by 125 publications

References 24 publications

Expression of hTERT immortalises normal human urothelial cells without inactivation of the p16/Rb pathway

Expression of hTERT immortalises normal human urothelial cells without inactivation of the p16/Rb pathway

Up-regulation of CIR1/CROC1 expression upon cell immortalization and in tumor-derived human cell lines

Down-Regulation of GATA-3 Expression during Human Papillomavirus-Mediated Immortalization and Cervical Carcinogenesis

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