Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug

• Published in: Oncogenesis (New York, NY) Vol. 2; no. 8; p. e66
• Main Authors: Tamminen, J A, Parviainen, V, Rönty, M, Wohl, A P, Murray, L, Joenväärä, S, Varjosalo, M, Leppäranta, O, Ritvos, O, Sengle, G, Renkonen, R, Myllärniemi, M, Koli, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2013; Nature Publishing Group
• Subjects: 631/67/1059/602; 631/67/1641; 692/420/755; Apoptosis; Cell Biology; Human Genetics; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Original; original-article; gremlin; mesothelioma; EMT; fibrillin; slug
• ISSN: 2157-9024; 2157-9024
• DOI: 10.1038/oncsis.2013.29

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.