MSLN gene silencing has an anti-malignant effect on cell lines overexpressing mesothelin deriving from malignant pleural mesothelioma.
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.
Department of Biology, University of Pisa, Pisa, Italy.
Ombretta
O
Melaiu
Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
Justin
J
Stebbing
Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
Ylenia
Y
Lombardo
Department of Biology, University of Pisa, Pisa, Italy.
Elisa
E
Bracci
Second Department of Pathology, Kansai Medical University, Moriguchi-Shi, Osaka, Japan.
Norihisa
N
Uehara
Department of Endocrinology and Metabolism, Orthopedics and Traumatology, Occupational Medicine, University of Pisa, Pisa, Italy.
Alessandra
A
Bonotti
Department of Endocrinology and Metabolism, Orthopedics and Traumatology, Occupational Medicine, University of Pisa, Pisa, Italy.
Alfonso
A
Cristaudo
Department of Endocrinology and Metabolism, Orthopedics and Traumatology, Occupational Medicine, University of Pisa, Pisa, Italy.
Rudy
R
Foddis
Laboratory of Clinical Oncology, Vercelli National Health Trust, Vercelli, Italy.
Luciano
L
Mutti
Department of Biology, University of Pisa, Pisa, Italy.
Roberto
R
Barale
Department of Biology, University of Pisa, Pisa, Italy.
Federica
F
Gemignani
Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
Georgios
G
Giamas
Department of Biology, University of Pisa, Pisa, Italy.
Stefano
S
Landi
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D000090204:Mesothelin; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D009361:Neoplasm Invasiveness; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology
D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; D000090204:Mesothelin