Distinct profiles of critically short telomeres are a key determinant of different chromosome aberrations in immortalized human cells: whole-genome evidence from multiple cell lines

Deng, Wen; Tsao, Sai Wah; Guan, Xin Yuan; Lucas, Joe N.; Hua, Xin; Leung, C. M.; Mak, Priscilla Hoi-Shan; Wang, Li Dong; Cheung, Annie L.M.

doi:10.1038/sj.onc.1208119

Cited by 57 publications

(59 citation statements)

References 50 publications

(54 reference statements)

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“…NP69, an SV40 Tantigen-immortalized nasopharyngeal epithelial cell line with many features of normal nasopharyngeal epithelial cells was used as a 'normal' control for NPC (Tsao et al, 2002). Two immortalized normal esophageal epithelial cell lines (NE1, NE3) (Deng et al, 2004;Ying et al, 2006) were used as 'normal' controls for esophageal carcinoma. Two HPVimmortalized human normal foreskin keratinocyte cell lines (FK16A at passage 88 and FK16B at passage 70) (Steenbergen et al, 2004) were also used as controls.…”

Section: Methodsmentioning

confidence: 99%

The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation

Seng¹,

Low²,

et al. 2006

Oncogene

125

118

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Identification of tumor suppressor genes (TSG) silenced by methylation uncovers mechanisms of tumorigenesis and identifies new epigenetic tumor markers for early cancer detection. Both nasopharyngeal carcinoma (NPC) and esophageal carcinoma are major tumors in Southern China and Southeast Asia. Through expression subtraction of NPC, we identified Deleted in Liver Cancer 1 (DLC1)/ARHGAP7 (NM_006094) -an 8p22 TSG as a major downregulated gene. Although expressed in all normal tissues, DLC1 was silenced or downregulated in 11/12 (91%) NPC, 6/15 (40%) esophageal, 5/8 (63%) cervical and 3/9 (33%) breast carcinoma cell lines. No genetic deletion of DLC1 was detected in NPC although a hemizygous deletion at 8p22-11 was found by 1-Mb array-CGH in some cell lines. We then located the functional DLC1 promoter by 5 0 -RACE and promoter activity assays. This promoter was frequently methylated in all downregulated cell lines and in a large collection of primary tumors including 89% (64/72) NPC (endemic and sporadic types), 51% (48/94) esophageal, 87% (7/8) cervical and 36% (5/14) breast carcinomas, but seldom in paired surgical marginal tissues and not in any normal epithelial tissue. The transcriptional silencing of DLC1 could be reversed by 5-aza-2 0 -deoxycytidine or genetic double knock-out of DNMT1 and DNMT3B. Furthermore, ectopic expression of DLC1 in NPC and esophageal carcinoma cells strongly inhibited their colony formation. We thus found frequent epigenetic silencing of DLC1 in NPC, esophageal and cervical carcinomas, and a high correlation of methylation with its downregulation, suggesting a predominant role of epigenetic inactivation. DLC1 appears to be a major TSG implicated in the pathogenesis of these tumors, and should be further tested as a molecular biomarker in patients with these cancers. Oncogene (2007) 26, 934-944.

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Section: Methodsmentioning

confidence: 99%

The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation

Seng¹,

Low²,

et al. 2006

Oncogene

125

118

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“…Metaphases were harvested and chromosome spreads prepared as described (24). Telomere quantitative fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY) were done sequentially as previously reported (25). At each PD analyzed, 20 and 100 metaphases were analyzed by quantitative FISH and SKY, respectively.…”

Section: Methodsmentioning

confidence: 99%

Transforming Growth Factor β1 Promotes Chromosomal Instability in Human Papillomavirus 16 E6E7–Infected Cervical Epithelial Cells

et al. 2008

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Uterine cervical cancer, the second most frequently occurring cancer in women worldwide, is tightly associated with the expression of high-risk human papillomavirus [mainly human papillomavirus (HPV)-16 and HPV18] oncogenes E6 and E7 and characteristically exhibits chromosomal instability. However, the mechanisms underlying chromosomal instability in cervical cancer are still not fully understood. In this study, we observed that two of three human cervical epithelial cell lines expressing HPV16 E6E7 became immortalized without extensive chromosomal instability and crisis. The introduction of transforming growth factor (TGF)-B1, a multiple functional cytokine/growth factor, in the culture medium induced crisis, which was associated with massive chromosomal end-to-end fusions and other structural aberrations. The distributions of structural aberrations on individual chromosomes were significantly correlated with the profiles of telomere signal-free ends. The immortalized cells that emerged from the TGF-B1-induced crisis showed multiple clonal structural aberrations that were not observed in cells without TGF-B1 treatment. Overexpression of the catalytic subunit of telomerase (hTERT) abolished the effects of TGF-B1 on chromosomal instability. Interestingly, another HPV16 E6E7-expressing cervical cell line that experienced crisis and telomere dysfunction under ordinary culture condition had a higher level of autocrine TGF-B1 production than the other two crisis-free immortalized cell lines. Blocking the TGF-B1 pathway by an inhibitor of TGF-B1 receptor type I prevented the crisis and telomere-mediated chromosomal instability. In addition, more dramatic telomere shortening was observed in cervical intraepithelial neoplasias having higher expression of TGF-B1 in vivo. These results together suggest an important role of TGF-B1 in the early process of cervical carcinogenesis. [Cancer Res 2008;68(17):7200-9]

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“…KYSE30/70/140/ 150/180/270/410/450/510/520 (Shimada et al, 1992) and TTn (Takahashi et al, 1990) came from Japanese patients and are available commercially from DSMZ (Braunschweig, Germany). NE1 is an immortalized esophageal epithelial cell line established by retroviral expression of HPV16 E6/E7 and served as the positive control in expression studies (Deng et al, 2004). MCH903.1, MCH910.7, and MCH924.4 are the donor cells used for the fusion experiments.…”

Section: Cell Lines and Culture Conditionsmentioning

confidence: 99%

Identification of a tumor suppressive critical region mapping to 3p14.2 in esophageal squamous cell carcinoma and studies of a candidate tumor suppressor gene, ADAMTS9

Leung

Kwok

et al. 2006

Oncogene

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Distinct profiles of critically short telomeres are a key determinant of different chromosome aberrations in immortalized human cells: whole-genome evidence from multiple cell lines

Cited by 57 publications

References 50 publications

The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation

The major 8p22 tumor suppressor DLC1 is frequently silenced by methylation in both endemic and sporadic nasopharyngeal, esophageal, and cervical carcinomas, and inhibits tumor cell colony formation

Transforming Growth Factor β1 Promotes Chromosomal Instability in Human Papillomavirus 16 E6E7–Infected Cervical Epithelial Cells

Identification of a tumor suppressive critical region mapping to 3p14.2 in esophageal squamous cell carcinoma and studies of a candidate tumor suppressor gene, ADAMTS9

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