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Genes involved in the carcinogenetic mechanisms underlying malignant pleural mesothelioma (MPM) are still poorly characterized. So far, mesothelin (MSLN) has aroused the most interest. It encodes for a membrane glycoprotein, frequently over-expressed in various malignancies such as MPM, and ovarian and pancreatic cancers. It has been proposed as a diagnostic and immunotherapeutic target with promising results. However, an alternative therapeutic approach seems to rise, whereby synthetic molecules, such as antisense oligonucleotides, could be used to inhibit MSLN activity. To date, such a gene-level inhibition has been attempted in two studies only, both on pancreatic and ovarian carcinoma cell lines, with the use of silencing RNA approaches. With regard to MPM, only one cell line (H2373) has been employed to study the effects of MSLN depletion. Indeed, the knowledge on the role of MSLN in MPM needs expanding. Accordingly, we investigated the expression of MSLN in a panel of three MPM cell lines, i.e. NCI-H28, Mero-14, and IstMes2; one non-MPM cell line was used as reference (Met5A). MSLN knock-down experiments on MSLN-overexpressing cells were also performed through silencing RNA (siRNA) to verify whether previous findings could be generalized to a different set of cell cultures. In agreement with previous studies, transient MSLN-silencing caused decreased proliferation rate and reduced invasive capacity and sphere formation in MSLN-overexpressing Mero-14 cells. Moreover, MSLN-siRNA combined with cisplatin, triggered a marked increase in apoptosis and a decrease in proliferation as compared to cells treated with each agent alone, thereby suggesting a sensitizing effect of siRNA towards cisplatin. In summary, our findings confirm that MSLN should be considered a key molecular target for novel gene-based targeted therapies of cancer.

In Fig 4A, the incorrect image is used for siMSLN-1. Please see the correct Fig 4 here.

Malignant Pleural Mesothelioma (MPM) is a cancer whit a poor prognosis. The landscape of the chromosomal rearrangements in MPM was approached by several authors but robust conclusions could not be made, given the limited sample sets analyzed within each study. In order to improve the knowledge on the field, we retrieved and pooled all the results deriving from published studies where comparative genomic hybridization (CGH) was employed. A total of 283 tissues (149 epithelioid, 53 sarcomatoid, 78 biphasic, and 3 unclassified) were analysed, 179 with classical chromosome CGH (cCGH), and 104 with arrayed-CGH (aCGH). Some chromosomal bands were involved in aberrations with a frequency exceeding 20% (-1p21,-9p,-14q, and-22q for the epithelioid,-4, +5p, +8q21ter,-9p,-13, and-14q for the sarcomatoid, and-9p,-14q, and-22q for the biphasic type). We found a statistical significant association between contemporary losses at 9p21 and 1p21-1p22 (21% of the samples showed losses at both bands, P=7.74x10-8), whose significance should be elucidated with further studies. Candidate cancer genes involved in MPM were suggested. Finally, 15% of epithelioid, 13% of sarcomatoid, and 13% of biphasic MPM tissues did not show any genomic alteration. Only two previous studies suggested a less aggressive behavior of MPM in relation to a low degree of chromosomal alterations. Thus, more work is warranted to understand whether chromosomal rearrangements could be included as prognostic biomarker in the clinical practice.

No abstract