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.
- Cancer driving gene
ASJC Scopus subject areas
- Molecular Biology
- Computer Science Applications
- Physical and Theoretical Chemistry
- Organic Chemistry
- Inorganic Chemistry