Human bronchial epithelial cells with integrated SV40 virus T antigen genes retain the ability to undergo squamous differentiation

Ke, Yang; Reddel, Roger R.; Gerwin, Brenda I.; Miyashita, Masao; McMenamin, Mary G.; Lechner, John F.; Harris, Curtis C.

doi:10.1111/j.1432-0436.1988.tb00592.x

Cited by 160 publications

(103 citation statements)

References 34 publications

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“…This effect was undoubtedly caused by TGF-b 1 itself as it was dose-dependent and could be blocked by the addition of a neutralizing anti-TGF-b 1 antibody. The downregulation of SLPI could be a mere consequence of cell differentiation, as the used bronchial epithelial cell line may undergo squamous differentiation when exposed to TGF-b 1 [21,37]. However, the concentrations of TGF-b 1 in these experiments were 10 times higher than the ones used in the current study and thus exceeded, by far, the physiological range.…”

Section: Discussionmentioning

confidence: 68%

“…The cell line used, BEAS-2B, is a simian vacuolating virus-40 transformed bronchial epithelial cell line established from healthy lung epithelium [20]. BEAS-2B shows and maintains typical epithelial cell morphology and function [21]. Therefore, BEAS-2B cells serve as an established model to investigate the pathogenesis of epithelial cell injury in airway diseases [22].…”

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confidence: 99%

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Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line

Jaumann¹,

Elssner²,

Mazur³

et al. 2000

Eur Respir J

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Obliterative bronchiolitis (OB) is the major long-term complication following lung and heart-lung transplantation. In bronchoalveolar lavage fluid samples obtained from patients suffering from OB, a marked increase in the number of neutrophils and elevated expression of transforming growth factor (TGF)-b 1 had been found. The goal of the study was to evaluate whether TGF-b 1 is capable of interfering with the expression of the secretory leukoprotease inhibitor (SLPI), the dominating defence of the conducting airways against neutrophil elastase (NE).The authors analysed the effects of TGF-b 1 on gene expression and protein release of SLPI by cultured human bronchial epithelial (BEAS-2B) cells. SLPI protein levels in the supernatants were quantified with a specific enzyme-linked immunosorbent assay; SLPI messenger ribonucleic acid (mRNA) levels were measured by reverse transcriptase polymerase chain reaction.Incubation with TGF-b 1 induced a marked decrease in SLPI protein levels (1 ng . mL and NE also caused a significant reduction in SLPI synthesis (10 ng . mL -1 TGF-b 1 + 7.5 U . mL -1 NE: mRNA SI = 0.61, p<0.05; protein SI = 0.65, p<0.05; 50 ng . mL -1 TGF-b 1 + 7.5 U . mL -1 NE: mRNA SI = 0.52, p<0.05; protein SI = 0.58, p<0.05; 10 ng . mL -1 TGF-b 1 : mRNA SI = 0.33, p<0.01; protein SI = 0.38, p<0.01). In conclusion, the data suggest that the coincidence of neutrophilia and upregulation of transforming growth factor-b 1 in obliterative bronchiolitis may lead to uninhibited neutrophil elastase activity by downregulation of secretory leukoprotease inhibitor, with the consequence of ongoing injury to the epithelium. Eur Respir J 2000; 15: 1052±1057.

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Section: Discussionmentioning

confidence: 68%

mentioning

confidence: 99%

Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line

Jaumann¹,

Elssner²,

Mazur³

et al. 2000

Eur Respir J

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“…The cells retain epithelial features, grow indefinitely in culture, express the SV40 large T, show minimal karyotypic changes, retain the ability to undergo squamous differentiation, and are not able to form tumors in nude mice (13,15). Interestingly, it was shown recently that expression of the SV40 early region was an essential first event in the multistep transformation of primary normal human lung epithelial cells (16,17).…”

Section: Resultsmentioning

confidence: 99%

Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus

Danilkovitch‐Miagkova

Duh

Kuzmin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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The candidate tumor-suppressor gene hyaluronidase 2 (HYAL2) encodes a glycosylphosphatidylinositol-anchored cell-surface protein that serves as an entry receptor for jaagsiekte sheep retrovirus, a virus that causes contagious lung cancer in sheep that is morphologically similar to human bronchioloalveolar carcinoma. The viral envelope (Env) protein alone can transform cultured cells, and we hypothesized that Env could bind and sequester the HYAL2 receptor and thus liberate a potential oncogenic factor bound and negatively controlled by HYAL2. Here we show that the HYAL2 receptor protein is associated with the RON receptor tyrosine kinase (also called MST1R or Stk in the mouse), rendering it functionally silent. In human cells expressing a jaagsiekte sheep retrovirus Env transgene, the Env protein physically associates with HYAL2. RON liberated from the association with HYAL2 becomes functionally active and consequently activates the Akt and mitogen-activated protein kinase pathways leading to oncogenic transformation of immortalized human bronchial epithelial cells. We find activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer.

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“…To explore the effects of these three genes on premalignant lung epithelial cells, we performed experiments with normal human lung epithelial cells immortalized by SV40 large T antigen, i.e., BEAS-2B cells (19). Individual and pairwise combinations of the three candidate driver genes were retrovirally transduced into BEAS-2B cells.…”

Section: The 14q133 Amplicon Contains Three Transcription Factor Genesmentioning

confidence: 99%

Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer

Kendall

Liu

Bakleh

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

202

211

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We used high-resolution array analysis to discover a recurrent lung cancer amplicon located at 14q13.3. Low-level gain of this region was detected in 15% of lung cancer samples, and high-level amplification was detected in an additional 4% of samples. Highlevel focal amplification appears to be specific to lung cancers, because it was not detected in >500 samples of other tumor types. Mapping of the commonly amplified region revealed there are three genes in the core region, all of which encode transcription factors with either established lung developmental function (TTF1/ NKX2-1, NKX2-8) or potential lung developmental function (PAX9). All three genes were overexpressed to varying degrees in amplified samples, although TTF1/NKX2-1 was not expressed in the squamous cancer subtype, consistent with previous reports. Remarkably, overexpression of any pairwise combination of these genes showed pronounced synergy in promoting the proliferation of immortalized human lung epithelial cells. Analysis of human lung cancer cell lines by both RNAi and ectopic overexpression further substantiates an oncogenic role for these transcription factors. These results, taken together with previous reports of oncogenic alterations of transcription factors involved in lung development (p63, CEBPA), suggest genetic alterations that directly interfere with transcriptional networks normally regulating lung development may be a more common feature of lung cancer than previously realized.gene amplification ͉ lung development ͉ lung oncogene ͉ TTF1 NKX2-8 PAX9 ͉ lineage addiction

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Human bronchial epithelial cells with integrated SV40 virus T antigen genes retain the ability to undergo squamous differentiation

Cited by 160 publications

References 34 publications

Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line

Transforming growth factor-β1 is a potent inhibitor of secretory leukoprotease inhibitor expression in a bronchial epithelial cell line

Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus

Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer

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