Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma

Our plain-English summary of Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma, by Y.L. Yang, J. Ni, P.C. Hsu, et al (Journal of Cellular and Molecular Medicine, 2015).

The study

• Authors: Y.L. Yang, J. Ni, P.C. Hsu, J.H. Mao, D. Hsieh, A. Xu, G. Chan, A. Au, Z. Xu, D.M. Jablons, L. You
• Journal: Journal of Cellular and Molecular Medicine
• Published: 2015;19(10):2385-96
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (mesothelioma) is a highly aggressive cancer without an effective treatment. Cul4A, a scaffold protein that recruits substrates for degradation, is amplified in several human cancers, including mesothelioma. We have recently shown that Cul4A plays an oncogenic role in vitro and in a mouse model. In this study, we analysed clinical mesothelioma tumours and found moderate to strong expression of Cul4A in 70.9% (51/72) of these tumours, as shown by immunohistochemistry. In 72.2% mesothelioma tumours with increased Cul4A copy number identified by fluorescence in situ hybridization analysis, Cul4A protein expression was moderate to strong. Similarly, Cul4A was overexpressed and Cul4A copy number was increased in human mesothelioma cell lines. Because Gli1 is highly expressed in human mesothelioma cells, we compared Cul4A and Gli1 expression in mesothelioma tumours and found their expression associated (P < 0.05, chi-square). In mesothelioma cell lines, inhibiting Cul4A by siRNA decreased Gli1 expression, suggesting that Gli1 expression is, at least in part, regulated by Cul4A in mesothelioma cells. Our results suggest a linkage between Cul4A and Gli1 expression in human mesothelioma.

© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

In plain English

This laboratory study looked at a protein called Cul4A in malignant pleural mesothelioma. The authors stained tumour samples from 73 patients having surgery, normal pleural tissue from 10 of them, and several mesothelioma cell lines. Of 72 tumours that could be assessed, 70.9% (51/72) showed moderate to strong Cul4A staining. Among 18 tumour samples with 3 to 4 copies of the Cul4A gene, 13 (72.2%) showed moderate to strong staining. Mesothelioma cell lines carried three or 3 to 4 copies of the gene. A laboratory-grown human mesothelial cell line, LP-9, and human lymphocytes carried two. Across 71 tumours and seven cell lines, Cul4A staining was statistically associated with staining for a second protein, Gli1 (P less than 0.05). Lowering Cul4A in cell lines reduced Gli1 levels. The study did not examine asbestos exposure. The authors concluded that Cul4A overexpression is associated with Gli1 expression and that their results provide a rationale for developing treatments targeting Cul4A. They noted that their gene-copy counts in tumours may be underestimates.

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 of surgical tumour samples (tissue microarrays stained by immunohistochemistry, gene copy counting by FISH) plus cell-culture experiments
• Who was studied: Primary malignant pleural mesothelioma samples from 73 patients undergoing surgical resection (normal pleural tissue from 10 of them as controls), studied under a University of California, San Francisco review board approval; also human mesothelioma cell lines, a mesothelial cell line (LP-9) and a lung cancer cell line (H1299)
• Exposure: No asbestos or other environmental exposure was studied. The laboratory experiments lowered Cul4A in cells using siRNA, or raised it in cells engineered to overexpress Cul4A.
• Main results:
  • Of 72 tumour samples (one missing), Cul4A staining was negative in 9.7% (7/72), weak in 19.4% (14/72) and moderate to strong in 70.9% (51/72)
  • Of the 10 normal pleural tissues, Cul4A staining was negative in 50% and strong in 10%
  • Among 18 tumour sections with 3 to 4 copies of Cul4A, 13 (72.2%) had moderate to strong Cul4A staining
  • Mesothelioma cell lines MS-1 and H28 had 3 to 4 copies of Cul4A, and H226, H2452, H290 and 211H had three copies. The cultured human mesothelial cell line LP-9 and human lymphocytes had two copies.
  • In 71 tumours and seven cell lines analysed together, Cul4A and Gli1 staining were significantly associated (P less than 0.05, chi-square test). Of the 28 samples with strong Cul4A, 42.9% had moderate and 14.3% had strong Gli1 staining.
  • After Cul4A was lowered by siRNA, Gli1 mRNA fell by 53% in H2452 cells and by 31% to 36% in 211H or MS-1 cells
  • Lowering Cul4A significantly reduced Gli reporter activity in H1299 lung cancer cells. In H290 mesothelioma cells the decrease was not significant (P = 0.05).
  • Gli1 protein decreased in MS-1, 211H and H28 cells after Cul4A was lowered. mTOR protein was 3.5-fold higher in H28 cells engineered to overexpress Cul4A.
  • Of tumours with subtype information (42 epithelioid, two sarcomatous, eight biphasic), there was no difference between subtypes in Cul4A or Gli1 protein or in Cul4A copy number
• The authors' conclusion: The authors concluded that increased Cul4A expression, which they suggest is driven by increased copy number, is associated with Gli1 expression in mesothelioma tumours and cells. They concluded that the mTOR pathway is involved and that their study provides a rationale for developing therapies targeting Cul4A.
• Limitations the authors state:
  • Gene copy counts in tumour tissue may be underestimates, because the analysis was done in interphase and the probes are hard to see in tissue sections
  • Increased Cul4A in tumours may partly be due to other mechanisms not studied
  • The proposed mechanism linking Cul4A, mTOR and Gli1 is a hypothesis needing further study

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma, Immunohistochemistry, Fluorescence In Situ Hybridization (FISH).

Related studies

• Cul4A is an oncogene in malignant pleural mesothelioma — M.S. Hung, J.H. Mao, et al. (2011)
• Targeting YAP in malignant pleural mesothelioma — W.Q. Zhang, Y.Y. Dai, et al. (2017)
• Gli as a novel therapeutic target in malignant pleural mesothelioma — H. Li, N. Lui, et al. (2013)
• Targeting of the Hedgehog signal transduction pathway suppresses survival of malignant pleural mesothelioma cells in vitro — M. You, J. Varona-Santos, et al. (2014)
• Inhibition of yes-associated protein down-regulates PD-L1 (CD274) expression in human malignant pleural mesothelioma — P.C. Hsu, J. Miao, et al. (2018)
• The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies — J. Hannah, P.B. Zhou (2013)

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