title: Gremlin-1 associates with fibrillin microfibrils in vivo and regulates mesothelioma cell survival through transcription factor slug.
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.
authors: 1] Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland [2] Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: J A
authors: JA
authors: Tamminen
authors: V
authors: V
authors: Parviainen
authors: M
authors: M
authors: Rönty
authors: A P
authors: AP
authors: Wohl
authors: L
authors: L
authors: Murray
authors: S
authors: S
authors: Joenväärä
authors: M
authors: M
authors: Varjosalo
authors: O
authors: O
authors: Leppäranta
authors: O
authors: O
authors: Ritvos
authors: G
authors: G
authors: Sengle
authors: R
authors: R
authors: Renkonen
authors: M
authors: M
authors: Myllärniemi
authors: K
authors: K
authors: Koli
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