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Tamminen JA, Parviainen V, Rönty M, et al. Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug. Oncogenesis. 2013;2:e66doi: 10.1038/oncsis.2013.29.
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. (2013). Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug. Oncogenesis, 2e66. https://doi.org/10.1038/oncsis.2013.29
Tamminen, J A, et al. "Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug." Oncogenesis vol. 2 (2013): e66. doi: https://doi.org/10.1038/oncsis.2013.29
Tamminen JA, Parviainen V, Rönty M, Wohl AP, Murray L, Joenväärä S, Varjosalo M, Leppäranta O, Ritvos O, Sengle G, Renkonen R, Myllärniemi M, Koli K. Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug. Oncogenesis. 2013 Aug 26;2:e66. doi: 10.1038/oncsis.2013.29. PMID: 23978876; PMCID: PMC3759128.
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Oncogenesis. 2013 Aug 26;2:e66. doi: 10.1038/oncsis.2013.29.

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

Oncogenesis

J A Tamminen, V Parviainen, M Rönty, A P Wohl, L Murray, S Joenväärä, M Varjosalo, O Leppäranta, O Ritvos, G Sengle, R Renkonen, M Myllärniemi, K Koli

Affiliations

  1. 1] Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland [2] Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.

PMID: 23978876 PMCID: PMC3759128 DOI: 10.1038/oncsis.2013.29

Abstract

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.

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