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.
Highlights
Lung cancer and pleural mesothelioma are two of the most deadly forms of cancer
We tested the expression of MSLN in established human lung cancer cell lines (H460 and A549) and mesothelioma cell line (H2052)
When compared to normal human lung epithelial cell line (BEAS-2B) and mesothelial cell line (MeT 5A), expression of MSLN was highly elevated in the cancer cell lines (Fig. 1c and d), suggesting a carcinogenic role of MSLN in lung cancer and mesothelioma
Summary
The prognosis of lung cancer and mesothelioma is extremely poor due to limited treatment modalities and lack of understanding of the disease mechanisms. Mesothelin (MSLN), a plasma membrane differentiation antigen, is expressed at a high level in many human solid tumors, including 70% of lung cancer and most mesotheliomas. Smoking rates (a risk factor for lung cancer) have decreased over the years and asbestos (a major cause of mesothelioma) usage in construction has been prohibited, the incidence of lung cancer and mesothelioma is still high, possibly due to their long latency period of development after initial exposure and the complexity and diversity of new carcinogens [3, 4]. Despite significant advances in treatment management, the prognosis of lung cancer and mesothelioma remains very poor due to limited treatment options and lack of understanding of the disease mechanisms. Identifying the key underlying molecular mechanisms of oncogenesis is essential for early detection and treatment of the diseases
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