Latent TGF-β binding proteins (LTBPs) 1 and 3 differentially regulate transforming growth factor-β activity in malignant mesothelioma
Autor: | Pamela Lindholm, Katri Koli, Marjukka Myllärniemi, Vuokko L. Kinnula, Jorma Keski-Oja, Ylermi Soini, Kaisa Salmenkivi, Piia Vehviläinen |
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Rok vydání: | 2010 |
Předmět: |
Mesothelioma
Pathology medicine.medical_specialty medicine.medical_treatment Pleural Neoplasms Down-Regulation Gene Expression Kaplan-Meier Estimate Smad2 Protein Biology medicine.disease_cause Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine Stroma Transforming Growth Factor beta Cell Line Tumor TGF beta signaling pathway medicine Gene silencing Humans Epithelial–mesenchymal transition Gene Silencing RNA Messenger RNA Small Interfering 030304 developmental biology 0303 health sciences Growth factor medicine.disease respiratory tract diseases 3. Good health Latent TGF-beta Binding Proteins 030220 oncology & carcinogenesis Cancer research Carcinogenesis Transforming growth factor |
Zdroj: | Human pathology. 42(2) |
ISSN: | 1532-8392 |
Popis: | 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. |
Databáze: | OpenAIRE |
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