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

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 tar...

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Published inOncogenesis (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
LanguageEnglish
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
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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.
AbstractList 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.
Author Myllärniemi, M
Murray, L
Varjosalo, M
Rönty, M
Koli, K
Renkonen, R
Tamminen, J A
Wohl, A P
Ritvos, O
Sengle, G
Parviainen, V
Joenväärä, S
Leppäranta, O
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/23978876$$D View this record in MEDLINE/PubMed
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Keywords gremlin
mesothelioma
EMT
fibrillin
slug
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Snippet Malignant mesothelioma is a form of cancer that is highly resistant to conventional cancer therapy for which no major therapeutic advances have been...
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SubjectTerms 631/67/1059/602
631/67/1641
692/420/755
Apoptosis
Cell Biology
Human Genetics
Internal Medicine
Medicine
Medicine & Public Health
Oncology
Original
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Title Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug
URI https://link.springer.com/article/10.1038/oncsis.2013.29
https://www.ncbi.nlm.nih.gov/pubmed/23978876
https://www.proquest.com/docview/1788355151
https://search.proquest.com/docview/1790961032
https://pubmed.ncbi.nlm.nih.gov/PMC3759128
Volume 2
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