The promyelocytic leukemia zinc-finger gene, PLZF, is frequently downregulated in malignant mesothelioma cells and contributes to cell survival

Our plain-English summary of The promyelocytic leukemia zinc-finger gene, PLZF, is frequently downregulated in malignant mesothelioma cells and contributes to cell survival, by M. Cheung, J. Pei, Y. Pei, et al (Oncogene, 2010).

The study

• Authors: M. Cheung, J. Pei, Y. Pei, S.C. Jhanwar, H.I. Pass, J.R. Testa
• Journal: Oncogene
• Published: 2010;29(11):1633-40
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

DNA copy number analysis was performed, using single-nucleotide polymorphism mapping arrays, to fine map genomic imbalances in human malignant mesothelioma (MM) cell lines derived from primary tumors. Chromosomal losses accounted for the majority of genomic imbalances. All 22 cell lines examined showed homozygous deletions of 9p21.3, centering at the CDKN2A/ARF and CDKN2B loci. Other commonly underrepresented segments included 1p36, 1p22, 3p21-22, 4q13, 4q34, 11q23, 13q12-13, 14q32, 15q15, 18q12, and 22q12, each observed in 55-90% of cell lines. Focal deletions of 11q23 encompassed the transcriptional repressor gene promyelocytic leukemia zinc finger (PLZF), which was validated by analysis of genomic DNA using real-time polymerase chain reaction (PCR). Semi-quantitative RT-PCR and immunoblot analysis revealed that PLZF is greatly downregulated in MM cell lines compared with non-malignant mesothelial cells. Ectopic expression of PLZF in PLZF-deficient MM cells resulted in decreased cell viability, reduced colony formation, as well as increased apoptosis, the latter based on results of various cell death assays and the observation of increased cleavage of caspase 3, PARP, and Mcl-1. These data indicate that deletions of PLZF are a common occurrence in MM and that downregulation of PLZF may contribute to MM pathogenesis by promoting cell survival.

In plain English

In this laboratory study, the authors examined 22 cell lines grown from the tumors of newly diagnosed, previously untreated people with malignant mesothelioma (MM). Using DNA arrays, they looked for stretches of chromosomes that were lost or gained. Losses were more common than gains. All 22 cell lines had lost both copies of a region on chromosome 9 (9p21.3) holding the CDKN2A/ARF and CDKN2B genes. A region on chromosome 11 (11q23.2-23.3) was lost in 64% of the lines. This region contains a gene called PLZF, and 11 of the 22 lines showed predicted loss of heterozygosity (LOH), based on genotype analysis, in the 11q region around it. PLZF levels, measured as RNA and as protein, were much lower in MM cell lines than in non-cancerous mesothelial cells, including in several lines without obvious deletions. When the authors added PLZF back into MM cell lines lacking it, the cells were less viable, formed fewer colonies and showed more signs of programmed cell death (apoptosis). The cells did not, however, stop progressing through the cell division cycle. The authors concluded that reduced PLZF is common in MM cells and may contribute to the disease by promoting cell survival. The study did not examine asbestos exposure.

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 human tumor cell lines (DNA copy number analysis and gene re-expression experiments)
• Who was studied: 22 malignant mesothelioma cell lines established from surgically removed tumors of newly diagnosed, previously untreated patients. Non-malignant mesothelial cells (LP9 and LP9/TERT-1) were used as controls. Tumor site (pleural or peritoneal) is not stated.
• Exposure: No asbestos exposure was studied. The experimental treatment was introduction of a PLZF gene expression construct (compared with an empty vector) into MM cell lines.
• Main results:
  • All 22 MM cell lines had homozygous deletions (loss of both copies) of 9p21.3, centered on the CDKN2A/ARF and CDKN2B genes.
  • Other frequent losses in the cell lines included 1p22.1-22.3 (82%), 3p22.1-p21.31 (77%) and 11q23.2-23.3 (64%).
  • Whole or large losses of chromosome 22 were seen in 78% of MM cell lines and of chromosome 4 in 53%.
  • Gains were less common than losses. A gain of 17q23.2 was seen in 55% of samples, and no recurrent sites of amplification were identified.
  • 11 of the 22 MM cell lines showed predicted loss of heterozygosity (LOH) in the 11q region containing PLZF, based on Affymetrix allele analysis. Separately, real-time PCR of genomic DNA was reported to validate hemizygous deletion of PLZF (data not shown), without stating in which lines.
  • PLZF was greatly downregulated in MM cell lines compared with non-malignant mesothelial cells, including in several lines without obvious deletions at the PLZF locus.
  • Re-expressing PLZF in PLZF-deficient MM cell lines greatly decreased colony numbers compared with empty vector. The difference was statistically significant (p less than 0.05).
  • In four MM cell lines, PLZF transfection increased apoptosis (p less than 0.05). It also increased cleaved Mcl-1, cleaved caspase-3 and cleaved PARP.
  • Re-expression of PLZF did not cause cell cycle arrest and did not decrease expression of MYC or cyclin A.
• The authors' conclusion: The authors concluded that downregulation of PLZF is common in MM cells and may contribute to the development of MM by promoting cell survival.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Homozygous Deletion, CDKN2A, Mesothelial Cells, Apoptosis.

Related studies

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• Usp9x- and Noxa-mediated Mcl-1 downregulation contributes to pemetrexed-induced apoptosis in human non-small-cell lung cancer cells — J. Yan, N. Zhong, et al. (2014)
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• A cluster of familial malignant mesothelioma with del(9p) as the sole chromosomal anomaly — M. Musti, D. Cavone, et al. (2002)
• Gli as a novel therapeutic target in malignant pleural mesothelioma — H. Li, N. Lui, et al. (2013)

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