Frequent coamplification and cooperation between C-MYC and PVT1 oncogenes promote malignant pleural mesothelioma

Our plain-English summary of Frequent coamplification and cooperation between C-MYC and PVT1 oncogenes promote malignant pleural mesothelioma, by E. Riquelme, M.B. Suraokar, J. Rodriguez, et al (Journal of Thoracic Oncology, 2014).

The study

• Authors: E. Riquelme, M.B. Suraokar, J. Rodriguez, B. Mino, H.Y. Lin, D.C. Rice, A. Tsao, I.I. Wistuba
• Journal: Journal of Thoracic Oncology
• Published: 2014;9(7):998-1007
• Cited by: 85 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Malignant pleural mesothelioma (MPM) is a deadly disease with poor prognosis and few treatment options. We characterized and elucidated the roles of C-MYC and PVT1 involved in the pathogenesis of MPM.

Methods: We used small interfering RNA (siRNA)-mediated knockdown in MPM cell lines to determine the effect of C-MYC and PVT1 abrogation on MPM cells undergoing apoptosis, proliferation, and cisplatin sensitivity. We also characterized the expression of microRNAs spanning the PVT1 region in MPM cell lines. Copy number analysis was measured by quantitative polymerase chain reaction and fluorescence in situ hybridization.

Results: Copy number analysis revealed copy number gains (CNGs) in chromosomal region 8q24 in six of 12 MPM cell lines. MicroRNA analysis showed high miR-1204 expression in MSTO-211H cell lines with four copies or more of PVT1. Knockdown by siRNA showed increased PARP-C levels in MSTO-211H transfected with siPVT1 but not in cells transfected with siC-MYC. C-MYC and PVT1 knockdown reduced cell proliferation and increased sensitivity to cisplatin. Analysis of the expression of apoptosis-related genes in the MSTO-211H cell line suggested that C-MYC maintains a balance between proapoptotic and antiapoptotic gene expression, whereas PVT1 and, to a lesser extent, miR-1204 up-regulate proapoptotic genes and down-regulate antiapoptotic genes. Fluorescence in situ hybridization analysis of MPM tumor specimens showed a high frequency of both CNGs (11 of 75) and trisomy (three copies; 11 of 75) for the C-MYC locus.

Conclusion: Our results suggest that C-MYC and PVT1 CNG promotes a malignant phenotype of MPM, with C-MYC CNG stimulating cell proliferation and PVT1 both stimulating proliferation and inhibiting apoptosis.

In plain English

This laboratory study examined two neighbouring chromosome 8 genes, C-MYC and PVT1, in malignant pleural mesothelioma (MPM). It used 12 cell lines (one a normal control) and 75 surgical tumor samples from M. D. Anderson Cancer Center. Asbestos exposure was not studied. One test found extra C-MYC copies in 6 of 12 cell lines; a second test found extra copies of both genes together in the same 5 of 12 lines. In MSTO-211H cells, switching down C-MYC or PVT1 slowed proliferation. It also lowered the cisplatin concentration needed to halve cell survival, 1.9-fold and 1.7-fold respectively. H28 cells showed no such slowing. In MSTO-211H, switching down PVT1 raised cell-death markers; H28 showed no change in one such marker. Among tumors, 11 of 75 had four or more C-MYC copies and 11 had three. No sarcomatoid tumor had four or more copies; 2 of 12 had three. Gains showed no correlation with patient outcome, possibly, the authors said, owing to limited follow-up data. The authors concluded that their cell-line findings suggest C-MYC gains stimulate proliferation and PVT1 gains stimulate proliferation and suppress cell death.

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 MPM cell lines and archived surgically resected MPM tumor specimens (gene copy number, gene expression and gene knockdown experiments)
• Who was studied: 75 MPM tumor samples of different histologic subtypes (37 epithelioid, 26 biphasic, 12 sarcomatoid), randomly selected from the tissue bank at The University of Texas M. D. Anderson Cancer Center, plus 12 cell lines. The article calls all 12 MPM cell lines, but elsewhere describes one (HCC-4012, also written HCT-4012) as a normal control mesothelial line. Dates are not given.
• Exposure: Asbestos exposure was not studied. Asbestos is mentioned only as background in the introduction. The study examined copy number and expression of the C-MYC and PVT1 genes.
• Main results:
  • One of the 12 cell lines, HCC-4012, was described as a normal control (a telomerase-transformed pleural mesothelial cell line)
  • In the 12 cell lines, FISH found copy number gain (four or more copies) of the C-MYC locus in 6 of 12 (50%)
  • In the 12 cell lines, q-PCR found C-MYC copy number gain (four or more copies) in 5 of 12 (42%) and PVT1 copy number gain in 5 of 12 (42%)
  • By q-PCR, C-MYC and PVT1 copy number gains always occurred in the same five cell lines (H2452, MET-5A, H2052, HP10 and MSTO-211H)
  • In the MSTO-211H cell line, knocking down C-MYC and PVT1 significantly inhibited cell proliferation
  • In the MSTO-211H cell line, knockdown of C-MYC and PVT1 caused a 1.9-fold (p less than 0.05) and 1.7-fold (p less than 0.05) decrease, respectively, in the cisplatin IC50 (the concentration that halves cell survival)
  • In the H28 cell line, knocking down C-MYC and PVT1 did not inhibit cell proliferation
  • In the MSTO-211H cell line, PVT1 knockdown increased cleaved PARP and cleaved caspase 3, which are markers of programmed cell death (apoptosis)
  • In the H28 cell line, no changes in cleaved PARP were detected under any treatment
  • In the MSTO-211H cell line, blocking miR-1204 produced no significant differences in cisplatin sensitivity or proliferation compared with control cells
  • In the 75 tumor samples, FISH found C-MYC copy number gain (four or more copies) in 11 of 75 (15%) and trisomy (three copies) in 11 of 75 (15%)
  • In the tumors, C-MYC copy number gains of four or more copies were seen in biphasic (6 of 26, 23%) and epithelioid (5 of 37, 13%) tumors but not in sarcomatoid tumors
  • In the tumors, C-MYC trisomy (three copies) was seen in biphasic (6 of 26, 23%), epithelioid (3 of 37, 8%) and sarcomatoid (2 of 12, 17%) tumors
  • In the patients whose tumors were tested, multivariate analysis showed no correlation between C-MYC copy number gains and patient outcome (p greater than 0.75)
  • C-MYC and PVT1 gene expression differed significantly between tumor samples and normal tissues (p less than 0.05)
• The authors' conclusion: The authors concluded that their findings, which came from gene knockdown experiments in cell lines, suggest the two genes have differing functions. In their reading, C-MYC copy gains stimulate proliferation and help decrease sensitivity to cisplatin. PVT1 copy gains stimulate proliferation, decrease sensitivity to platinum therapy and suppress apoptosis.
• Limitations the authors state:
  • The authors suggested that the lack of correlation with clinical features and outcome may be due to the difficulty of obtaining detailed treatment and long-term follow-up data for these patients

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, Prognosis, Apoptosis, Cisplatin, Fluorescence In Situ Hybridization (FISH).

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