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 and cell lines. Here, we deepened the study on nine of them (ASS1, EIF4G1, GALNT7, GLUT1, IGF2BP3 (IMP3), ITGA4, RAN, SOD1, and THBS2) 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.
Highlights
Malignant pleural mesothelioma (MPM) is a rare occupational disease mainly due to asbestos handling [1,2,3,4]
We evaluated whether ASS1, EIF4G1, GALNT7, GLUT1, IGF2BP3 (IMP3), ITGA4, RAS signaling pathway (RAN), SOD1, and THBS2 could be bone fide cancer driving genes (CDGs) of pleural tumorigenesis
In this study ASS1, EIF4G1, GALNT7, GLUT1, IGF2BP3, ITGA4, RAN, SOD1, and THBS2 genes were assayed on Mero-14, Mero-25, IST-Mes2, and NCI-H28, and the phenotypic changes were evaluated following gene silencing depending upon the mRNA expression
Summary
Malignant pleural mesothelioma (MPM) is a rare occupational disease mainly due to asbestos handling [1,2,3,4]. Novel diagnostic and therapeutic targets for MPM are urgently needed. For this purpose, in the recent past we undertook research for identifying mesothelial cancer driving genes (CDGs), since the deregulation of normal transcription levels is one of the mechanisms driving tumorigenesis. In order to confirm the status of these genes, we performed a preliminary screening by comparing their expression in 15 surgically resected MPMs and in 20 non-malignant pleura tissues. As a further criterion for discriminating CDGs from PGs, in the same study we analyzed the mRNA expression of these 51 genes on two MPM cell lines, ending with a short list of 28 genes
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