Identification of pregnancy-associated plasma protein A as a migration-promoting gene in malignant pleural mesothelioma cells: a potential therapeutic target

Our plain-English summary of Identification of pregnancy-associated plasma protein A as a migration-promoting gene in malignant pleural mesothelioma cells: a potential therapeutic target, by J. Huang, S. Tabata, S. Kakiuchi, et al (Oncotarget, 2013).

The study

• Authors: J. Huang, S. Tabata, S. Kakiuchi, T. The Van, H. Goto, M. Hanibuchi, Y. Nishioka
• Journal: Oncotarget
• Published: 2013;4(8):1172-84
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Despite recent advances in treatment, malignant pleural mesothelioma (MPM) remains a deadly disease. Targeted therapy generated broad interests and is highly expected for the treatment of MPM, yet promising preclinical results have not been translated into substantial clinical benefits for the patients. In this study, we tried to identify the genes which play functional roles in cell migration as well as to test whether they can be used as novel targets for molecular targeted therapy for MPM in preclinical model. In our study, pregnancy-associated plasma protein A (PAPPA) was identified as a gene whose expression level is correlated with MPM cell migration by correlation analysis combining MPM cell migration ability and their gene expression profiles. Highly migratory cells were selected from MPM cell lines, MSTO-211H, NCI-H290 and EHMES-1 in vitro and up-regulation of PAPPA in these cells were confirmed. In vitro, PAPPA was demonstrated to stimulate the MPM cell migration via cleavage of insulin-like growth factor-binding protein-4 and subsequent release of IGF-1. Gene silencing of PAPPA in MPM cells led to reduced migration, invasion and proliferation. Furthermore, PAPPA shRNA transfected NCI-H290 when orthotopically inoculated into pleural cavity of severe combined immunodeficiency recipient mice, failed to develop tumors and produce bloody pleural effusion as control shRNA transfected cells did. Our study suggests that PAPPA plays a functional role in promoting MPM cell migration and it might serve as a potential therapeutic target for the treatment of MPM.

In plain English

This laboratory study used human malignant pleural mesothelioma (MPM) cell lines and a mouse model. The authors compared migration of eight MPM cell lines with their gene expression profiles and identified pregnancy-associated plasma protein A (PAPPA) as a gene whose expression correlated with migration; secreted PAPPA tended to correlate with migration (Pearson r = 0.7217, P = 0.0671). Cells selected in vitro for high migration (MSTO-211H, NCI-H290, Y-MESO-14) migrated roughly five-fold more than parental cells and expressed more PAPPA. Recombinant IGF-1 stimulated migration dose-dependently; IGFBP-4 blocked this, added PAPPA restored it, and an anti-IGF-1 antibody abolished the restoration. Silencing PAPPA with siRNA in three cell lines reduced migration and proliferation; stable shRNA silencing in NCI-H290 cells reduced migration, invasion and proliferation. When NCI-H290 cells were injected into the pleural cavity of SCID mice, control shRNA cells produced tumours in all recipients, with bloody pleural effusion in four of five mice, whereas PAPPA shRNA cells produced only traces of tumour and almost no effusion. The authors concluded that PAPPA can promote MPM cell migration and might be a therapeutic target.

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 (migration assays, gene expression microarray, gene silencing) plus an orthotopic xenograft mouse experiment
• Who was studied: Human malignant pleural mesothelioma cell lines (eight in the initial correlation analysis, drawn from MSTO-211H, NCI-H290, EHMES-1, Y-MESO-14, Y-MESO-5A, NCI-H28, NCI-H2052, NCI-H2373, NCI-H2452) and male SCID mice aged 6-7 weeks. The work was done at The University of Tokushima, Japan.
• Exposure: Not an exposure study. The experimental interventions were PAPPA gene silencing (siRNA and shRNA) and treatment of cells with recombinant human IGF-1, IGFBP-4, PAPPA and tPA. Asbestos is mentioned only as background to MPM.
• Main results:
  • Secreted PAPPA levels in conditioned medium of the MPM cell lines tended to correlate positively with migration ability (Pearson r = 0.7217, P = 0.0671)
  • Three cell lines selected in vitro for high migration (MSTO-211H, NCI-H290, Y-MESO-14) migrated about five times more than their parental lines and had higher PAPPA expression
  • In the MPM cell lines, IGF-1R and IGFBPs were expressed, with IGFBP3 and IGFBP4 dominant. No IGF1 mRNA or secreted IGF-1 was detected.
  • Recombinant PAPPA cleaved IGFBP-4 but not IGFBP-3, while tPA cleaved IGFBP-3 but not IGFBP-4
  • IGFBP-4 blocked IGF-1-induced migration, added PAPPA restored it, and an anti-IGF-1 antibody completely abrogated the enhanced migration (EHMES-1 and MSTO-211H)
  • siRNA silencing of PAPPA in NCI-H290, MSTO-211H and EHMES-1 significantly reduced migration
  • After siRNA silencing, growth inhibition became evident 72 h after treatment
  • In NCI-H290 stably transfected with PAPPA shRNA, invasion fell to 20-30% and migration to 30-40% of control shRNA cells
  • Proliferation of PAPPA shRNA-transfected NCI-H290 cells was slowed in vitro
  • In SCID mice, control shRNA NCI-H290 produced pleural tumours in all recipients, with bloody pleural effusion in four of five mice. PAPPA shRNA cells produced only traces of tumour and almost no effusion.
• The authors' conclusion: The authors concluded that PAPPA can act as a migration-promoting gene in MPM cells, partly through its proteolytic activity. They proposed that it might be used as a novel therapeutic target for MPM.
• Limitations the authors state:
  • The authors state they did not rule out nonproteolytic mechanisms for PAPPA's migration-promoting function
  • Adding PAPPA from outside barely rescued proliferation after PAPPA silencing, implying an additional, unexplained mechanism
  • Their failure to detect IGF-1 expression conflicted with earlier reports, and the reason for the discrepancy was not determined
  • NCI-H28 was dropped from later analyses because microarray and qRT-PCR results for PAPPA did not agree

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, Targeted Therapy, Pleural Cavity, Pleural Effusion.

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