Mesothelin Promotes Epithelial-to-Mesenchymal Transition and Tumorigenicity of Human Lung Cancer and Mesothelioma Cells

Details

• Journal Article:
  Mol Cancer
• Personal Author:
  He, Xiaoqing ; Wang, Liying ; Riedel, Heimo ; Wang, Kai ; Yang, Yong ; Dinu, Cerasela Z. ; Rojanasakul, Yon
• Description:
  Background
  
  Lung 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.
  
  Methods
  
  ShRNA 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.
  
  Results
  
  MSLN 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.
  
  Conclusions
  
  These 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.
  
  
• Subjects:
  Carcinogens Mesothelioma Neoplasms Respiratory System
• Keywords:
  Author Keywords: Mesothelin; Lung Cancer; Mesothelioma; Epithelial To Mesenchymal Transition; Cancer Stem Cells; Circulating Tumor Cells; Metastasis Mesothelial Cells; Mesothelioma; Tumor Inhibition; Therapeutic Agents; Cancer; Lung Cancer; Lung Cells; Pulmonary System Disorders; Respiratory System Disorders; Humans; Cellular Function; Metastasis; Pleural Cavity; Plasma Membrane; In Vitro Study; In Vivo Study; Bioassays; Cytometric Analysis; Immunoassays; Antigens; Cell Cultures; Cell Migration; Stem Cells; Cell Type; Gene Expression; Gene Regulation; Cellular Reactions; Oncogenic Agents;
• Source:
  Mol Cancer. 16.
• Pubmed ID:
  28288645
• Pubmed Central ID:
  PMC5348784
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  13 pdf pages
• Volume:
  16
• Issue:
  1
• NIOSHTIC Number:
  nn:20049535
• Federal Fiscal Year:
  2017
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Collection(s):
  CDC Public Access National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:7652553af52acc1b24dcc6603634941cbf2c80c3aa3a2b42b3523f5d12890436bab82be4afce8df64e0810c66a65427c7bc786300fd960cb6f93c2375d2a9bba
• Download URL:
  https://stacks.cdc.gov/view/cdc/44805/cdc_44805_DS1.pdf
• File Type:
  [PDF - 1.89 MB ]