Genetic and functional characterization of vWF and RMO1 involvement in osteosarcoma.
Published: 2005
Language: eng
Number of pages: 175
Description: Osteosarcomas are aggressive tumours with a 5-year survival rate of 60% for patients without overt metastases at diagnosis. A better understanding of osteosarcoma pathogenesis at the molecular level may result in improved treatment. I examined gene expression in osteosarcoma and observed that two genes were differentially expressed in 25 primary and metastatic tumour samples: the novel gene RMO1 (r&barbelow;educed expression in m&barbelow;etastatic o&barbelow;steosarcoma) and the von Willebrand factor (vWF) gene.vWF, previously considered to be expressed exclusively by endothelial cells and megakaryocytes, is involved in processes critical to hematogenous tumour cell metastasis to the lung. I found that vWF gene expression increased during tumour progression from primary tumour to metastasis and, unexpectedly, that vWF protein was expressed by osteosarcoma tumour cells in vivo . These findings suggest that vWF expression is deregulated in osteosarcoma, potentially contributing to metastasis.I observed that RMO1 expression decreased as tumours progressed to metastatases and, furthermore, that RMO1 exhibited frequent loss of heterozygosity in primary osteosarcoma samples, consistent with a role in cancer. RMO1 contains an open reading frame with multiple splice forms and encodes a protein with homology with the Grb7 family of adapter proteins. I determined that RMO1 is temporarily phosphorylated in response to serum treatment. Furthermore, I established that RMO1 interacts with vinculin, a cancer-related protein that regulates lamellipodia protrusion, and that the two proteins colocalize to the cellular leading edge. These results suggest RMO1 may act as an adapter protein and link cell signalling with regulation of lamellipodia, possibly through the novel interaction with vinculin. Taken together, these data are consistent with a possible role for RMO1  in inhibiting osteosarcoma progression.The comparison of gene expression in osteosarcoma tumour samples, and the further investigation of differentially expressed genes, has improved our understanding of osteosarcoma etiology. vWF is deregulated in osteosarcoma cells, suggesting a possible mechanism for osteosarcoma metastasis to the lung. Furthermore, the novel gene RMO1, observed to be frequently deleted and with altered expression in osteosarcoma metastases and a possible link between cell signalling and control of lamellipodia, may be a candidate for a protein involved in osteosarcoma development.
Notes: Source: Dissertation Abstracts International, Volume: 66-10, Section: B, page: 5210.

Thesis (Ph.D.)--University of Toronto, 2005.

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