title: Latent TGF-β binding proteins (LTBPs) 1 and 3 differentially regulate transforming growth factor-β activity in malignant mesothelioma.
abstract: Malignant mesothelioma is an aggressive cancer of the pleura with poor prognosis. There is a need to identify new biomarkers and therapeutic targets for this invasive and fatal disease. Transforming growth factor β (TGF-β) can promote mesothelioma tumorigenesis through multiple mechanisms. Latent TGF-β binding proteins (LTBPs) regulate TGF-β activation by targeting the growth factor into the extracellular matrix from where it can be released and activated. We investigated here the expression patterns of different LTBP isoforms in malignant mesothelioma tissues and in 2 established malignant mesothelioma cell lines. All LTBPs were expressed, but LTBP-3 was the main isoform in healthy pleura and in cultured nonmalignant mesothelial cells. We observed down-regulation of LTBP-3 expression in malignant mesothelioma, which was associated with high P-Smad2 levels indicative of TGF-β activity specifically in the tumor tissue. Small interfering RNA-mediated suppression of LTBP-3 expression in mesothelioma cells increased the secretion of TGF-β activity. Immunoreactivity of LTBP-1, on the other hand, was markedly strong in the tumor stroma, which showed significantly lower levels of P-Smad2. A strong negative correlation between LTBP-1 and P-Smad2 immunoreactivity was found, implying that LTBP-1 is not likely to contribute directly to the increased levels of TGF-β activity in malignant mesothelioma. Current results suggest that LTBPs 1 and 3 may have specific roles in malignant mesothelioma pathogenesis through the regulation of TGF-β activation in the tumor tissue and the structure of the tumor stroma.
authors.affiliation: Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, 00014 Helsinki, Finland.
authors.forename: Piia
authors.initials: P
authors.lastname: Vehviläinen
authors.forename: Katri
authors.initials: K
authors.lastname: Koli
authors.forename: Marjukka
authors.initials: M
authors.lastname: Myllärniemi
authors.forename: Pamela
authors.initials: P
authors.lastname: Lindholm
authors.forename: Ylermi
authors.initials: Y
authors.lastname: Soini
authors.forename: Kaisa
authors.initials: K
authors.lastname: Salmenkivi
authors.forename: Vuokko L
authors.initials: VL
authors.lastname: Kinnula
authors.forename: Jorma
authors.initials: J
authors.lastname: Keski-Oja
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation; D015870:Gene Expression; D020868:Gene Silencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: C509032:LTBP1 protein, human; C509038:LTBP3 protein, human; D053779:Latent TGF-beta Binding Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta