title: Transforming growth factor-β-induced protein (TGFBI) suppresses mesothelioma progression through the Akt/mTOR pathway.
abstract: As an uncommon cancer, mesothelioma is very hard to treat with a low average survival rate owing to its usual late detection and being highly invasive. The link between asbestos exposure and the development of mesothelioma in humans is unequivocal. TGFBI, a secreted protein that is induced by transforming growth factor-β in various human cell types, has been shown to be associated with tumorigenesis in various types of tumors. It has been demonstrated that TGFBI expression is markedly suppressed in asbestos-induced tumorigenic cells, while an ectopic expression of TGFBI significantly suppresses tumorigenicity and progression in human bronchial epithelial cells. In order to delineate a potential role of TGFBI in mediating the molecular events that occur in mesothelioma tumorigenesis, we generated stable TGFBI knockdown mutants from the mesothelium cell line Met-5A by using an shRNA approach, and secondly created ectopic TGFBI overexpression mutants from the mesothelioma cell line H28 in which TGFBI is absent. We observed that in the absence of TGFBI, the knockdown mesothelial and mesothelioma cell lines exhibited an elevated proliferation rate, enhanced plating efficiency, increased anchorage-independent growth, as well as an increased cellular protein synthesis rate as compared with their respective controls. Furthermore, cell cycle regulatory proteins c-myc/cyclin D1/phosphor-Rb were upregulated; a more active PI3K/Akt/mTOR signaling pathway was also detected in TGFBI-depleted cell lines. These findings suggest that TGFBI may repress mesothelioma tumorigenesis and progression via the PI3K/Akt signaling pathway.
authors.affiliation: Center for Radiological Research, College of Physicians & Surgeons, Columbia University Medical Center, New York, NY, USA.
authors.forename: Gengyun
authors.initials: G
authors.lastname: Wen
authors.forename: Mei
authors.initials: M
authors.lastname: Hong
authors.forename: Bingyan
authors.initials: B
authors.lastname: Li
authors.forename: Wupeng
authors.initials: W
authors.lastname: Liao
authors.forename: Simon K
authors.initials: SK
authors.lastname: Cheng
authors.forename: Burong
authors.initials: B
authors.lastname: Hu
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Calaf
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Partridge
authors.forename: Jian
authors.initials: J
authors.lastname: Tong
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
mesh_terms: D001194:Asbestos / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D008654:Mesothelioma / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D018301:Neoplasms, Mesothelial / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017232:Oncogene Proteins v-mos / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099222:betaIG-H3 Protein
chemical_list: D001194:Asbestos; D019938:Cyclin D1; D004268:DNA-Binding Proteins; D004815:Epidermal Growth Factor; D016326:Extracellular Matrix Proteins; D017232:Oncogene Proteins v-mos; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; C530104:CCND1 protein, human; C116115:MYCBP protein, human; C546842:MTOR protein, human