Differentially expressed genes in asbestos-induced tumorigenic human bronchial epithelial cells: implication for mechanism

Our plain-English summary of Differentially expressed genes in asbestos-induced tumorigenic human bronchial epithelial cells: implication for mechanism, by Y.L. Zhao, C.Q. Piao, L.J. Wu, et al (Carcinogenesis, 2000).

The study

• Authors: Y.L. Zhao, C.Q. Piao, L.J. Wu, M. Suzuki, T.K. Hei
• Journal: Carcinogenesis
• Published: 2000;21(11):2005-10
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Although exposure to asbestos fibers is associated with the development of lung cancer, the underlying mechanism(s) remains unclear. Using human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells, we previously showed that UICC chrysotiles can malignantly transform these cells in a stepwise fashion before they become tumorigenic in nude mice. In the present study we used cDNA expression arrays to screen differentially expressed genes among the tumorigenic cells. A total of 15 genes were identified, 11 of which were further confirmed by northern blot. Expression levels of these genes were then determined among transformed BEP2D cells at different stages of the neoplastic process, including non-tumorigenic cells that were resistant to serum-induced terminal differentiation, early and late passage transformed BEP2D cells, five representative tumor cell lines and fused tumorigenic-control cell lines which were no longer tumorigenic. A consistent 2- to 3-fold down-regulation of the DCC (deleted in colon cancer), Ku70 and heat shock protein 27 genes were detected in all the independently generated tumor cell lines while expression levels in early transformants as well as in the fusion cell lines remained normal. In contrast, all the tumor cell lines examined demonstrated 2- to 4-fold overexpression of the insulin receptor and its signal transduction genes. Differential expression of these genes was completely restored in the fusion cell lines examined. No alteration in c-jun or EGF receptor expression was found in any of the cell lines. Our data suggest that activation of the insulin receptor pathway and inactivation of DCC and Ku70 may cooperate in malignant transformation of BEP2D cells induced by asbestos.

In plain English

This laboratory study used human bronchial (airway) cells, not people. The cells, called BEP2D, had been made to keep dividing using human papillomavirus. Earlier, this laboratory had produced tumor-forming cell lines by treating them for 7 days with chrysotile asbestos at 4 µg/cm2. The authors compared expression of 588 known genes between these tumor-forming cells and untreated cells; 15 differed, and 11 were confirmed by a second test. In all five tumor cell lines, DCC, Ku70 and HSP27 expression was 2- to 3-fold lower than in controls, and eight genes, including the insulin receptor, showed 2- to 5-fold higher expression. Earlier-stage transformed cells mostly expressed these genes at control levels. The exceptions were higher c-fos in serum-resistant cells, higher insulin receptor in early- and late-passage cells, and higher NFκB and PISSLRE in late-passage cells. Five fusion clones of tumor and untreated cells formed no tumors in mice; in the four fusion lines examined, the expression differences largely disappeared. The authors concluded that reduced DCC and Ku70 may contribute to asbestos-induced malignant progression of these cells, and that more studies are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell study comparing gene expression with a cDNA array and northern blots, plus cell-fusion experiments with tumor tests in nude mice
• Who was studied: Human bronchial epithelial cells immortalized with human papillomavirus type 18 (BEP2D cells), including control cells, transformed cells at different stages, five tumor cell lines and fused cell lines; tumor formation was tested in male nude mice
• Exposure: Chrysotile asbestos fibers (UICC chrysotile), given as a single 7-day treatment at 4 µg/cm2 in earlier work that produced the tumorigenic cells
• Main results:
  • Of 588 known genes on the array, 15 were differentially expressed in the asbestos-induced tumorigenic cells compared with control cells
  • Northern blots, run on cells that included four fusion cell lines, confirmed 11 of the 15 genes
  • DCC, Ku70 and HSP27 expression was lowered 2- to 3-fold in all five tumor cell lines and was at control levels in the fusion cells
  • In serum-resistant transformed cells and in early and late passage cells, expression of DCC, Ku70 and HSP27 was comparable with controls
  • Eight genes (insulin receptor, SHB, Grb2, ERK2, c-fos, NFκB p50/105, Ets-like gene and PISSLRE) were overexpressed in all five tumor cell lines at 2- to 5-fold of controls
  • Overexpression of these eight genes was abrogated in all fusion cell lines examined
  • Insulin receptor expression was up about 1.5-fold in early and late passage transformed cells
  • Insulin receptor expression was up about 2.2-fold in all tumor cell lines
  • In Table III, c-fos was 3.89-fold on the cDNA array, 5.82-fold in non-tumorigenic (serum-resistant) cells, and unchanged in early and late passage cells
  • NFκB (p50) was overexpressed 1.7-fold in late passage transformed cells and 3-fold in all five tumor cell lines
  • In Table III, PISSLRE was 1.72-fold on the cDNA array, unchanged in non-tumorigenic and early passage cells, 2.09-fold in late passage cells, 1.97 on average in tumor cell lines, and 1.30 in fusion cells
  • Five independently derived fusion clones of tumorigenic and non-tumorigenic BEP2D cells were tested in nude mice, and none produced tumors
  • Fusion of tumor cells with tumor cells produced tumorigenic hybrids
  • No change was detected in expression of c-myc, ilk, EGFR, c-jun or fra-1, which another study had reported as up-regulated in rat mesothelioma
• The authors' conclusion: The authors concluded that reduced expression of DCC and Ku70 may contribute to the malignant progression of BEP2D cells induced by asbestos, possibly together with activation of the insulin receptor pathway, and that their findings provide some clues to the mechanism of fiber carcinogenesis
• Limitations the authors state:
  • The authors stated that additional studies are needed to determine how these multiple pathways are integrated in the target epithelium
  • The authors reported a 25% false-positive rate for the cDNA array, which they cross-checked with northern blots

Topics

The National Library of Medicine indexes this study under subjects our site covers: Chrysotile, Lung cancer.

Medical terms in this study, explained in our Lexicon: Lung Cancer, UICC, Chrysotile, Colorectal Cancer, Malignant Transformation.

Related studies

• Karyotype analysis of tumorigenic human bronchial epithelial cells transformed by chrysolite asbestos using chemically induced premature chromosome condensation technique — M. Suzuki, C.Q. Piao, et al. (2001)
• Malignant transformation of immortalized human bronchial epithelial cells by asbestos fibers — T.K. Hei, L.J. Wu, et al. (1997)
• Role of mesothelin in carbon nanotube-induced carcinogenic transformation of human bronchial epithelial cells — X. He, E. Despeaux, et al. (2016)
• Indications for distinct pathogenic mechanisms of asbestos and silica through gene expression profiling of the response of lung epithelial cells — T.N. Perkins, P.M. Peeters, et al. (2015)
• Effects of Chrysotile Exposure in Human Bronchial Epithelial Cells: Insights into the Pathogenic Mechanisms of Asbestos-Related Diseases — G.R. Gulino, M. Polimeni, et al. (2016)
• Role of PARP1 on DNA damage induced by mineral silicate chrysotile in bronchial epithelial and pleural mesothelial cells — M. Zhang, H. Xia, et al. (2021)

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