Cul4A is an oncogene in malignant pleural mesothelioma

Our plain-English summary of Cul4A is an oncogene in malignant pleural mesothelioma, by M.S. Hung, J.H. Mao, Z. Xu, et al (Journal of Cellular and Molecular Medicine, 2011).

The study

• Authors: M.S. Hung, J.H. Mao, Z. Xu, C.T. Yang, J.S. Yu, C. Harvard, Y.C. Lin, D.T. Bravo, D.M. Jablons, L. You
• Journal: Journal of Cellular and Molecular Medicine
• Published: 2011;15(2):350-8
• Cited by: 63 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Cullin 4A (Cul4A) is important in cell survival, development, growth and the cell cycle, but its role in mesothelioma has not been studied. For the first time, we identified amplification of the Cul4A gene in four of five mesothelioma cell lines. Consistent with increased Cul4A gene copy number, we found that Cul4A protein was overexpressed in mesothelioma cells as well. Cul4A protein was also overexpressed in 64% of primary malignant pleural mesothelioma (MPM) tumours. Furthermore, knockdown of Cul4A with shRNA in mesothelioma cells resulted in up-regulation of p21 and p27 tumour suppressor proteins in a p53-independent manner in H290, H28 and MS-1 mesothelioma cell lines. Knockdown of Cul4A also resulted in G0/G1 cell cycle arrest and decreased colony formation in H290, H28 and MS-1 mesothelioma cell lines. Moreover, G0/G1 cell cycle arrest was partially reversed by siRNA down-regulation of p21 and/or p27 in Cul4A knockdown H290 cell line. In the contrary, overexpression of Cul4A resulted in down-regulation of p21 and p27 proteins and increased colony formation in H28 mesothelioma cell line. Both p21 and p27 showed faster degradation rates in Cul4A overexpressed H28 cell line and slower degradation rates in Cul4A knockdown H28 cell line. Our study indicates that Cul4A amplification and overexpression play an oncogenic role in the pathogenesis of mesothelioma. Thus, Cul4A may be a potential therapeutic target for MPM.

© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

In plain English

This was a laboratory study of the gene Cul4A in mesothelioma cell lines grown in the lab and in tumour tissue removed during surgery for malignant pleural mesothelioma. It did not study asbestos or any other exposure. Using a fluorescent gene-labelling method (FISH), the authors found extra copies of the Cul4A gene in four of five mesothelioma cell lines compared with normal cells. Cul4A protein was increased in 9 of 14 (64.3%) mesothelioma tissue specimens. When the authors reduced Cul4A in three mesothelioma cell lines, two growth-braking proteins, p21 and p27, rose. More cells stalled in the G0/G1 phase of the cell cycle, and the cells formed significantly fewer colonies. Lowering p21 and/or p27 partly reversed this stalling in one cell line. Adding extra Cul4A to one cell line lowered p21 and p27, sped their breakdown and increased colony formation. The authors concluded that Cul4A amplification may be an oncogenic (cancer-promoting) event in mesothelioma and called for future study of Cul4A as a treatment target. The article gives conflicting tumour counts.

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 study using human mesothelioma cell lines and surgically removed tumour tissue (gene copy counting by FISH, protein measurement by Western blot, gene knockdown and overexpression experiments)
• Who was studied: Five human mesothelioma cell lines (NCI-H28, MSTO-211H, REN, NCI-H290, MS-1), a normal mesothelial cell line (LP9), p53-null HCT116 colon cancer cells, and malignant pleural mesothelioma and adjacent normal pleural tissue from patients having surgery. Pathologic diagnosis was confirmed at the University of California, San Francisco. The text gives eight primary tumours in one place and 14 mesothelioma tissue specimens in another.
• Exposure: No asbestos or other fiber exposure was studied. The experimental manipulation was lowering Cul4A with shRNA (and lowering p21 and/or p27 with siRNA), or overexpressing Cul4A, in mesothelioma cell lines.
• Main results:
  • Four of five mesothelioma cell lines (MS-1, H290, 211H and H28) had increased Cul4A gene copy numbers compared with normal lymphocytes and normal mesothelial (LP9) cells.
  • Cul4A protein was increased in 9 of 14 (64.3%) malignant pleural mesothelioma specimens.
  • Lowering Cul4A raised p21 and p27 protein levels in all mesothelioma cell lines studied. p53 rose only in MS-1 cells, which the authors took to suggest a p53-independent effect in H290 and H28 cells.
  • Lowering Cul4A led to significantly more cells in the G0/G1 phase (H290 and H28 at 0, 2 and 8 hours; MS-1 at 8 hours). Colony numbers were significantly lower in H290, H28 and MS-1 cells than in controls.
  • In H290 cells with Cul4A lowered, reducing p21 and/or p27 partially reversed the G0/G1 arrest at 96 hours.
  • Overexpressing Cul4A in H28 cells lowered p21 and p27 and produced significantly more colonies than in controls.
  • In H28 cells, p21 and p27 broke down faster when Cul4A was overexpressed and slower when Cul4A was lowered, compared with empty-vector controls.
• The authors' conclusion: The authors concluded that amplification of Cul4A may be an oncogenic event in mesothelioma development. They wrote that future studies of Cul4A as a prognostic and therapeutic target in malignant pleural mesothelioma are warranted.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma.

Related studies

• Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma — Y.L. Yang, J. Ni, et al. (2015)
• Signal transducer and activator of transcription 1 (STAT1) acts like an oncogene in malignant pleural mesothelioma — L. Arzt, H. Kothmaier, et al. (2014)
• The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies — J. Hannah, P.B. Zhou (2013)
• Identification of novel candidate oncogenes and tumor suppressors in malignant pleural mesothelioma using large-scale transcriptional profiling — G.J. Gordon, G.N. Rockwell, et al. (2005)
• Oncogenes and tumor-suppressor genes in mesothelioma--a synopsis — J.F. Lechner, J. Tesfaigzi, et al. (1997)
• Tumorigenicity of human mesothelial cell line transfected with EJ-ras oncogene — R.R. Reddel, L. Malan-Shibley, et al. (1989)

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