Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug
| Autor: | L. Murray, Olli Ritvos, Outi Leppäranta, Risto Renkonen, Alexander P. Wohl, Katri Koli, Jenni A. Tamminen, Mikko Juhani Rönty, Sakari Joenväärä, Markku Varjosalo, Marjukka Myllärniemi, Gerhard Sengle, Ville Parviainen |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty fibrillin gremlin Biology medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation medicine Mesothelioma Molecular Biology 030304 developmental biology 0303 health sciences Tumor microenvironment Cell growth EMT Cancer Cell cycle medicine.disease respiratory tract diseases 3. Good health Pemetrexed slug mesothelioma 030220 oncology & carcinogenesis Cancer research Original Article Carcinogenesis medicine.drug |
| Zdroj: | Oncogenesis |
| ISSN: | 2157-9024 |
| Popis: | Malignant mesothelioma is a form of cancer that is highly resistant to conventional cancer therapy for which no major therapeutic advances have been introduced. Here, we identify gremlin-1, a known bone morphogenetic protein inhibitor crucial for embryonic development, as a potential therapeutic target for mesothelioma. We found high expression levels of gremlin-1 in the mesothelioma tumor tissue, as well as in primary mesothelioma cells cultured from pleural effusion samples. Downregulation of gremlin-1 expression by siRNA-mediated silencing in a mesothelioma cell line inhibited cell proliferation. This was associated with downregulation of the transcription factor slug as well as mesenchymal proteins linked to cancer epithelial-to-mesenchymal transition. Further, resistance to paclitaxel-induced cell death was associated with high gremlin-1 and slug expression. Treatment of gremlin-1-silenced mesothelioma cells with paclitaxel or pemetrexed resulted in efficient loss of cell survival. Finally, our data suggest that concomitant upregulation of fibrillin-2 in mesothelioma provides a mechanism for extracellular localization of gremlin-1 to the tumor microenvironment. This was supported by the demonstration of interactions between gremlin-1, and fibrillin-1 and -2 peptides as well as by colocalization of gremlin-1 to fibrillin microfibrils in cells and tumor tissue samples. Our data suggest that gremlin-1 is also a potential target for overcoming drug resistance in mesothelioma. |
| Databáze: | OpenAIRE |
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