Abstract
During the development of the nervous system, guidance cues are required to correctly direct the developing axons. These cues are highly conserved in evolution and may have diverse functions and receptors. The Slit proteins are members of these cues and along with their roundabout (robo) receptors, they act as repulsive cues for robo-expressing axons preventing them from crossing or re-crossing the midline. There is increasing evidence that the slit-robo interactions are not limited to axon guidance. The repulsive effect on axons due to slit-robo binding is mirrored in the immune system as well as in breast tumour cells; Slit proteins act as inhibitors of cell migration and invasion. Our group recently demonstrated that both SLIT and ROBO genes are inactivated in human cancers by promoter region CpG island hypermethylation with the subsequent silencing of gene expression. Restoring expression after treatment with a demethylating agent, provided further evidence that promoter hypermethylation was responsible for silencing SLIT-ROBO genes in several human cancers. Whilst Robo1 homozygous mutant mice die at birth due to incomplete lung development, the heterozygous mice show increased predisposition to tumour development concurrent with the inactivation of the remaining wild type Robo1 allele by promoter region CpG island hypermethylation. SEMA3B, another axon guidance molecule, was recently demonstrated to be epigenetically inactivated in human cancers and suppressed tumour growth. Hence, evidence is accumulating for the role of axon guidance molecules in human cancer development. Unlike mutational inactivation, epigenetic inactivation is a reversible event. This presents new and exciting opportunities for clinical management of cancer. In addition, promoter hypermethylation of genes is increasingly being developed as molecular biomarkers for non-invasive screens for early detection of cancer. Furthermore, the SLIT(s) gene products are secretary proteins, which may also lead to the development of novel therapeutic approaches. This chapter summarises the literature on SLIT-ROBO gene families in relation to human diseases.
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Dallol, A., Dickinson, R.E., Latif, F. (2005). Epigenetic Disruption of the SLIT-ROBO Interactions in Human Cancer. In: Esteller, M. (eds) DNA Methylation, Epigenetics and Metastasis. Cancer Metastasis — Biology and Treatment, vol 7. Springer, Dordrecht. https://doi.org/10.1007/1-4020-3642-6_8
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