Abstract
Bone morphogenetic proteins (BMPs) are known to play an important role in melanoma development and progression. However, the downstream targets of BMPs have not been investigated thus far. Therefore, we treated melanoma cell lines with the Smad-specific BMP inhibitor Dorsomorphin and performed a cDNA microarray. We identified death inducer-obliterator 1 (Dido1) as a BMP-specific Smad-regulated target gene, which was confirmed by qRT–PCR, immunofluorescence staining and electrophoretic mobility shift assay experiments. An analysis of Dido1 expression revealed an upregulation of Dido1 levels in melanoma cell lines and tissues compared with normal melanocytes. Colony-formation assays showed that siDido1-transfected cells formed significantly smaller colonies when grown in soft agar compared with control cells. In addition, fluorescence-activated cell sorting and western blot experiments revealed that transfection of melanoma cells with Dido1 small interfering RNAs led to an upregulation of apoptosis. Furthermore, cell migratory and invasive potentials were strongly reduced in siDido1-transfected cells compared with control cells. Finally, we demonstrated that Dido1 induces the expression of Integrin αV, thereby promoting the attachment, migration, invasion and apoptosis resistance of melanoma cells.
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References
Houghton AN, Polsky D . Focus on melanoma. Cancer Cell 2002; 2: 275–278.
Sieber C, Kopf J, Hiepen C, Knaus P . Recent advances in BMP receptor signaling. Cytokine Growth Factor Rev 2009; 20: 343–355.
Yamaguchi K, Nagai S, Ninomiya-Tsuji J, Nishita M, Tamai K, Irie K et al. XIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathway. EMBO J 1999; 18: 179–187.
Gazzerro E, Canalis E . Bone morphogenetic proteins and their antagonists. Rev Endocr Metab Disord 2006; 7: 51–65.
Anderson GJ, Darshan D . Small-molecule dissection of BMP signaling. Nat Chem Biol 2008; 4: 15–16.
Hogan BL . Bone morphogenetic proteins in development. Curr Opin Genet Dev 1996; 6: 432–438.
Thawani JP, Wang AC, Than KD, Lin CY, La Marca F, Park P . Bone morphogenetic proteins and cancer: review of the literature. Neurosurgery 2010; 66: 233–246; discussion 246.
Rothhammer T, Poser I, Soncin F, Bataille F, Moser M, Bosserhoff AK . Bone morphogenic proteins are overexpressed in malignant melanoma and promote cell invasion and migration. Cancer Res 2005; 65: 448–456.
Rothhammer T, Bataille F, Spruss T, Eissner G, Bosserhoff AK . Functional implication of BMP4 expression on angiogenesis in malignant melanoma. Oncogene 2007; 26: 4158–4170.
Boergermann JH, Kopf J, Yu PB, Knaus P . Dorsomorphin and LDN-193189 inhibit BMP-mediated Smad, p38 and Akt signalling in C2C12 cells. Int J Biochem Cell Biol 2010; 42: 1802–1807.
Garcia-Domingo D, Leonardo E, Grandien A, Martinez P, Albar JP, Izpisua-Belmonte JC et al. DIO-1 is a gene involved in onset of apoptosis in vitro, whose misexpression disrupts limb development. Proc Natl Acad Sci USA 1999; 96: 7992–7997.
Rojas AM, Sanchez-Pulido L, Futterer A, van Wely KH, Martinez AC, Valencia A . Death inducer obliterator protein 1 in the context of DNA regulation. Sequence analyses of distant homologues point to a novel functional role. FEBS J 2005; 272: 3505–3511.
Hsu MY, Rovinsky S, Penmatcha S, Herlyn M, Muirhead D . Bone morphogenetic proteins in melanoma: angel or devil? Cancer Metastasis Rev 2005; 24: 251–263.
Busch C, Drews U, Eisele SR, Garbe C, Oppitz M . Noggin blocks invasive growth of murine B16-F1 melanoma cells in the optic cup of the chick embryo. Int J Cancer 2008; 122: 526–533.
Na YR, Seok SH, Kim DJ, Han JH, Kim TH, Jung H et al. Bone morphogenetic protein 7 induces mesenchymal-to-epithelial transition in melanoma cells, leading to inhibition of metastasis. Cancer Sci 2009; 100: 2218–2225.
Hendrix MJ, Seftor EA, Hess AR, Seftor RE . Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 2003; 3: 411–421.
Peters KG, Kontos CD, Lin PC, Wong AL, Rao P, Huang L et al. Functional significance of Tie2 signaling in the adult vasculature. Recent Prog Horm Res 2004; 59: 51–71.
Cavallaro U, Christofori G . Molecular mechanisms of tumor angiogenesis and tumor progression. J Neurooncol 2000; 50: 63–70.
Rothhammer T, Braig S, Bosserhoff AK . Bone morphogenetic proteins induce expression of metalloproteinases in melanoma cells and fibroblasts. Eur J Cancer 2008; 44: 2526–2534.
Garcia-Domingo D, Ramirez D, Gonzalez de Buitrago G, Martinez AC . Death inducer-obliterator 1 triggers apoptosis after nuclear translocation and caspase upregulation. Mol Cell Biol 2003; 23: 3216–3225.
Vachon PH . Integrin signaling, cell survival, and anoikis: distinctions, differences, and differentiation. J Signal Transduct 2011; 2011: 738137.
Frisch SM, Ruoslahti E . Integrins and anoikis. Curr Opin Cell Biol 1997; 9: 701–706.
Zhang Y, Yang M, Ji Q, Fan D, Peng H, Yang C et al. Anoikis induction and metastasis suppression by a new integrin alphavbeta3 inhibitor in human melanoma cell line M21. Invest New Drugs 2011; 29: 666–673.
Ivanov VN, Bhoumik A, Ronai Z . Death receptors and melanoma resistance to apoptosis. Oncogene 2003; 22: 3152–3161.
Rockmann H, Schadendorf D . Drug resistance in human melanoma: mechanisms and therapeutic opportunities. Onkologie 2003; 26: 581–587.
Kuphal S, Bauer R, Bosserhoff AK . Integrin signaling in malignant melanoma. Cancer Metastasis Rev 2005; 24: 195–222.
Hood JD, Cheresh DA . Role of integrins in cell invasion and migration. Nat Rev Cancer 2002; 2: 91–100.
Marshall JF, Hart IR . The role of alpha v-integrins in tumour progression and metastasis. Semin Cancer Biol 1996; 7: 129–138.
Moschos SJ, Drogowski LM, Reppert SL, Kirkwood JM . Integrins and cancer. Oncology (Williston Park) 2007; 21 (9 Suppl 3): 13–20.
Felding-Habermann B, Fransvea E, O’Toole TE, Manzuk L, Faha B, Hensler M . Involvement of tumor cell integrin alpha v beta 3 in hematogenous metastasis of human melanoma cells. Clin Exp Metastasis 2002; 19: 427–436.
Voura EB, Ramjeesingh RA, Montgomery AM, Siu CH . Involvement of integrin alpha(v)beta(3) and cell adhesion molecule L1 in transendothelial migration of melanoma cells. Mol Biol Cell 2001; 12: 2699–2710.
Koistinen P, Ahonen M, Kahari VM, Heino J . alphaV integrin promotes in vitro and in vivo survival of cells in metastatic melanoma. Int J Cancer 2004; 112: 61–70.
Braig S, Mueller DW, Rothhammer T, Bosserhoff AK . MicroRNA miR-196a is a central regulator of HOX-B7 and BMP4 expression in malignant melanoma. Cell Mol Life Sci 2010; 67: 3535–3548.
Rothhammer T, Hahne JC, Florin A, Poser I, Soncin F, Wernert N et al. The Ets-1 transcription factor is involved in the development and invasion of malignant melanoma. Cell Mol Life Sci 2004; 61: 118–128.
Trachana V, van Wely KH, Guerrero AA, Futterer A, Martinez AC . Dido disruption leads to centrosome amplification and mitotic checkpoint defects compromising chromosome stability. Proc Natl Acad Sci USA 2007; 104: 2691–2696.
Wenke AK, Grassel S, Moser M, Bosserhoff AK . The cartilage-specific transcription factor Sox9 regulates AP-2epsilon expression in chondrocytes. FEBS J 2009; 276: 2494–2504.
Arndt S, Poser I, Moser M, Bosserhoff AK . Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling. Mol Cell Neurosci 2007; 34: 603–611.
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92: 9363–9367.
Wenke AK, Kjellman C, Lundgren-Akerlund E, Uhlmann C, Haass NK, Herlyn M et al. Expression of integrin alpha10 is induced in malignant melanoma. Cell Oncol 2007; 29: 373–386.
Acknowledgements
We are indebted to Dr Carlos Martínez-Alonso (Madrid, Spain) for providing the Dido1 construct, Simone Kaufmann and Lisa Ellmann for excellent technical assistance and Dr Daniel Müller for helpful discussions throughout the work.
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Braig, S., Bosserhoff, AK. Death inducer-obliterator 1 (Dido1) is a BMP target gene and promotes BMP-induced melanoma progression. Oncogene 32, 837–848 (2013). https://doi.org/10.1038/onc.2012.115
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DOI: https://doi.org/10.1038/onc.2012.115
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