Eif4g1 and ran as possible drivers for malignant pleural mesothelioma

Irene Dell’anno, Marcella Barbarino, Elisa Barone, Antonio Giordano, Luca Luzzi, Maria Bottaro, Loredana Migliore, Silvia Agostini, Alessandra Melani, Ombretta Melaiu, Calogerina Catalano, Monica Cipollini, Roberto Silvestri, Alda Corrado, Federica Gemignani, Stefano Landi

Research output: Contribution to journalArticlepeer-review

Abstract

For malignant pleural mesothelioma (MPM) novel therapeutic strategies are urgently needed. In a previous study, we identified 51 putative cancer genes over-expressed in MPM tissues andcelllines. Here,wedeepenedthestudyonnineofthem(ASS1,EIF4G1,GALNT7,GLUT1,IGF2BP3 (IMP3),ITGA4,RAN,SOD1,andTHBS2)to ascertain whether they are truly mesothelial cancer driver genes(CDGs) or genes overexpressed in an adaptive response to the tumoral progression(“passenger genes”). Through a fast siRNA-based screening, we evaluated the consequences of gene depletion on migration, proliferation, colony formation capabilities, and caspase activities of four MPM (Mero-14, Mero-25, IST-Mes2, and NCI-H28) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model. The depletion of EIF4G1 and RAN significantly reduced cell proliferation and colony formation and increased caspase activity. In particular, the findings for RAN resemble those observed for other types of cancer. Thus, we evaluated the in vitro effects of importazole (IPZ), a small molecule inhibitor of the interaction between RAN and importin-β. We showed that IPZ could have effects similar to those observed following RAN gene silencing. We also found that primary cell lines from one out of three MPM patients were sensitive to IPZ. As EIF4G1 and RAN deserve further investigation with additional in vitro and in vivo studies, they emerged as promising CDGs, suggesting that their upregulation could play a role in mesothelial tumorigenesis and aggressiveness. Furthermore, present data propose the molecular pathways dependent on RAN as a putative pharmacological target for MPM patients in the view of a future personalized medicine.

Original languageEnglish
Article number4856
Pages (from-to)1-18
Number of pages18
JournalInternational Journal of Molecular Sciences
Volume21
Issue number14
DOIs
Publication statusPublished - Jul 2 2020

Keywords

  • Cancer driving gene
  • EIF4G1
  • Importazole
  • MPM
  • RAN
  • SiRNA

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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