Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells

Abstract

BackgroundLung cancer and pleural mesothelioma are two of the most deadly forms of cancer. The prognosis of lung cancer and mesothelioma is extremely poor due to limited treatment modalities and lack of understanding of the disease mechanisms. We have identified mesothelin as a potentially unique therapeutic target that as a specific advantage appears nonessential in most cell types. Mesothelin (MSLN), a plasma membrane differentiation antigen, is expressed at a high level in many human solid tumors, including 70% of lung cancer and nearly all mesotheliomas. However, the role of MSLN in the disease process and underlying mechanisms is largely unknown.MethodsShRNA knockdown and overexpression of MSLN were performed in human cancer cell lines and corresponding normal cells, respectively. Tumorigenic and metastatic effects of MSLN were examined by tumor sphere formation, migration, and invasion assays in vitro, as well as xenograft tumor assay in vivo. EMT and CSCs were detected by qPCR array, immunoblotting and flow cytometry.ResultsMSLN plays a key role in controlling epithelial-to-mesenchymal transition (EMT) and stem properties of human lung cancer and mesothelioma cells that control their tumorigenicity and metastatic potential. Firstly, MSLN was found to be highly upregulated in non-small cell lung cancer (NSCLC) patient tissues and in lung carcinoma and mesothelioma cell lines. Secondly, genetic knockdown of MSLN significantly reduced anchorage-independent cell growth, tumor sphere formation, cell adhesion, migration and invasion in vitro, as well as tumor formation and metastasis in vivo. Thirdly, ectopic overexpression of MSLN induced the malignant phenotype of non-cancerous cells, supporting its role as an oncogene. Finally, mechanistic studies revealed that knockdown of MSLN reversed EMT and attenuated stem cell properties, in addition to inhibiting tumor growth and metastasis.ConclusionsThese results indicate an essential role of MSLN in controlling EMT and stem cell properties of human lung cancer and mesothelioma cells. Since EMT is an important process in tumor progression and metastasis, and MSLN is nonessential in most normal tissue, our findings on MSLN may provide new insights into the disease mechanisms and may aid in the development of novel targeted therapy for lung cancer and mesothelioma.

Evaluation of soluble mesothelin-related peptides and MSLN genetic variability in asbestos-related diseases

“…It is involved in important cellular processes, including cell adhesion, proliferation, invasion, and epithelial-to-mesenchymal transition. 18,19 Mesothelin is a glycophosphatidylinositol-linked membrane protein, but it also has three isoforms that are present in the circulation. 12,15,20 Enzyme-linked immunosorbent assay (ELISA) can detect different isoforms, usually referred to as soluble mesothelin related peptides (SMRP).…”

Induction of Slug by Chronic Exposure to Single-Walled Carbon Nanotubes Promotes Tumor Formation and Metastasis

“…Many studies have demonstrated that EMT is associated with cell migration, invasion, and tumor progression; 32–35 however, it remains controversial whether Slug acts as a tumor promoter or tumor suppressor based on recent reports. 36,37 Our previous studies showed that SWCNT-transformed cells exhibit aggressive cancer phenotypes, including increased cell migration, invasion, and anchorage-independent cell growth.…”

Rapid evolution and biogeographic spread in a colorectal cancer

“…1C-D). Moreover, we also observed a clonal non-synonymous mutation in MSLN , a plasma membrane differentiation antigen which is emerging as an attractive target for cancer immunotherapy due to its potential involvement in the epithelial-to-mesenchymal transition, a cellular process thought to be required for metastatic dissemination 12 .…”