title: Role of mesothelin in carbon nanotube-induced carcinogenic transformation of human bronchial epithelial cells.
abstract: Carbon nanotubes (CNTs) have been likened to asbestos in terms of morphology and toxicity. CNT exposure can lead to pulmonary fibrosis and promotion of tumorigenesis. However, the mechanisms underlying CNT-induced carcinogenesis are not well defined. Mesothelin (MSLN) is overexpressed in many human tumors, including mesotheliomas and pancreatic and ovarian carcinomas. In this study, the role of MSLN in the carcinogenic transformation of human bronchial epithelial cells chronically exposed to single-walled CNT (BSW) was investigated. MSLN overexpression was found in human lung tumors, lung cancer cell lines, and BSW cells. The functional role of MSLN in the BSW cells was then investigated by using stably transfected MSLN knockdown (BSW shMSLN) cells. MSLN knockdown resulted in significantly decreased invasion, migration, colonies on soft agar, and tumor sphere formation. In vivo, BSW shMSLN cells formed smaller primary tumors and less metastases. The mechanism by which MSLN contributes to these more aggressive behaviors was investigated by using ingenuity pathway analysis, which predicted that increased MSLN could induce cyclin E expression. We found that BSW shMSLN cells had decreased cyclin E, and their proliferation rate was reverted to nearly that of untransformed cells. Cell cycle analysis showed that the BSW shMSLN cells had an increased G2 population and a decreased S phase population, which is consistent with the decreased rate of proliferation. Together, our results indicate a novel role of MSLN in the malignant transformation of bronchial epithelial cells following CNT exposure, suggesting its utility as a potential biomarker and drug target for CNT-induced malignancies.
authors.affiliation: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia;
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia;
authors.forename: Emily
authors.initials: E
authors.lastname: Despeaux
authors.affiliation: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia; HELD, National Institute for Occupational Safety and Health, Morgantown, West Virginia;
authors.forename: Todd A
authors.initials: TA
authors.lastname: Stueckle
authors.affiliation: WVU Cancer Institute, West Virginia University, Morgantown, West Virginia; and.
authors.forename: Alexander
authors.initials: A
authors.lastname: Chi
authors.affiliation: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia;
authors.forename: Vincent
authors.initials: V
authors.lastname: Castranova
authors.affiliation: Department of Chemical Engineering, West Virginia University, Morgantown, West Virginia.
authors.forename: Cerasela Zoica
authors.initials: CZ
authors.lastname: Dinu
authors.affiliation: HELD, National Institute for Occupational Safety and Health, Morgantown, West Virginia;
authors.forename: Liying
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia; WVU Cancer Institute, West Virginia University, Morgantown, West Virginia; and yrojan@hsc.wvu.edu.
authors.forename: Yon
authors.initials: Y
authors.lastname: Rojanasakul
mesh_terms: D000818:Animals; D055745:Bronchioles / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058851:GPI-Linked Proteins / Q000502:physiology*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D000090204:Mesothelin; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D037742:Nanotubes, Carbon / Q000633:toxicity*; D009368:Neoplasm Transplantation
chemical_list: D002273:Carcinogens; D019927:Cyclin E; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; C000715528:Msln protein, mouse; D037742:Nanotubes, Carbon; D000090204:Mesothelin
keywords: cancer; cell invasion; mesothelin; nanotubes; tumor formation