Disease relevance of SLIT2

• 2. In addition, SLIT2 expression was down-regulated in methylated breast tumors, relative to normal control, as demonstrated by quantitative real-time reverse transcription-PCR [1].
• SLIT2 promoter methylation was detected in 43% of breast cancer, 53% of non-small cell lung cancer, and 36% of small cell lung cancer primary tumors [1].
• Frequent epigenetic inactivation of the SLIT2 gene in gliomas [2].
• SLIT2 and SLIT3 mRNAs were co-expressed in embryonic stem (ES) cells with embryoid body formation, and diffuse type gastric cancer with signet ring cell features [3].
• SLIT2 axon guidance molecule is frequently inactivated in colorectal cancer and suppresses growth of colorectal carcinoma cells [4].

High impact information on SLIT2

• Furthermore, we show that human Slit2 can repel olfactory and hippocampal axons and collapse their growth cones [5].
• SLIT2 methylation was reversed and expression restored by treating colorectal tumor cell lines with the demethylating agent 5-aza-2-deoxycytidine [4].
• In contrast, normal colorectal mucosa from the same patients exhibited significantly lower levels of SLIT2 promoter region hypermethylation [4].
• We have shown recently that SLIT2 has tumor suppressor activity and that it is epigenetically silenced in >40% of lung and breast tumors [4].
• In this study, we have analyzed the methylation status of SLIT2 in primary colorectal cancers and matching normal colorectal mucosa [4].

Chemical compound and disease context of SLIT2

• The hypermethylation of the SLIT2 promoter region in glioma cell lines correlated with loss of expression and treatment with the demethylating agent 5-aza-2'-deoxycytidine reactivated SLIT2 gene expression [2].

Biological context of SLIT2

• These findings demonstrate that SLIT2 is frequently inactivated in lung and breast cancer by promoter region hypermethylation and allele loss and is an excellent candidate for the lung and breast tumor suppressor gene previously mapped to 4p15.2 [1].
• Our data indicate that SLIT2 is frequently inactivated by promoter region CpG island hypermethylation in gliomas and may be a good candidate for a glioma tumour suppressor gene (TSG) located at 4p15 [2].
• Loss of heterozygosity analysis revealed that SLIT2 methylated gliomas retained both alleles of a microsatellite marker within 100 kb of the SLIT2 gene at 4p15 [2].
• Comparative genomics on SLIT1, SLIT2, and SLIT3 orthologs [3].
• Here, comparative integromics analyses on SLIT1, SLIT2, and SLIT3 orthologs were performed by using bioinformatics [3].

Anatomical context of SLIT2

• SLIT2 promoter methylation was detected in 59% of breast cancer, 77% of non-small cell lung cancer, and 55% of small cell lung cancer cell lines [1].
• Recent evidence suggests that Slit2 protein may function in other settings because human and Xenopus Slit2 has been shown to inhibit leukocyte chemotaxis [1].
• In contrast, slit-2 inhibited DA neuron extensions and repelled DA neurite growth [6].
• In mice lacking slit1 and slit2, a subset of RGC axons extend into the telencephalon and grow along the pial surface but not more deeply into this tissue [7].
• Netrin-1 and slit-2 regulate and direct neurite growth of ventral midbrain dopaminergic neurons [6].

Associations of SLIT2 with chemical compounds

• We investigated the roles of netrin-1 and slit-2 in regulation and navigation of dopamine (DA) axon growth using an explant culture preparation of embryonic ventral midbrain (embryonic day 14) and a co-culture system [6].
• The ability of heparin oligosaccharides of defined structure (ranging in size from disaccharide to tetradeccasaccharide) to inhibit binding of a glypican-Fc fusion protein to recombinant human Slit-2 was determined using an ELISA [8].
• Exogenous Slit2 does not affect ureteric branching or nephron formation during kidney development [9].
• We show that Slit2, a neuronal repellent factor, is up-regulated in the skin by allergen sensitization and down-regulates the migration of Langerhans cells [10].
• Two additional potential leucine-rich repeat encoding exons were identified within intron 12 of Slit2 [11].

Regulatory relationships of SLIT2

• The rhombic lip and ventral midline express Slit2 and both early and late migrants are repelled by sources of Slit2 in co-culture [12].

Other interactions of SLIT2

• SLIT2 protein is a putative ligand for the ROBO receptors [1].
• Both SLIT1 and SLIT2 proteins show approximately 40% amino acid identity to slit and 60% identity to each other [13].
• Promoter region CpG island of SLIT2 was found to be methylated in 71% (5/7) of glioma cell lines and was unmethylated in five DNA samples from normal brain tissues [2].
• SLIT2-mediated ROBO2 signaling restricts kidney induction to a single site [14].
• Upon further elucidation, we observed that Slit-2 mediates the tumor-suppressive effect via a coordinated regulation of the beta-catenin and PI3K signaling pathways and by enhancing beta-catenin/E-cadherin-mediated cell-cell adhesion [15].

Analytical, diagnostic and therapeutic context of SLIT2

• In addition, SLIT2 expression was downregulated in methylated gliomas relative to unmethylated tumour samples, as demonstrated by quantitative real-time RT-PCR [2].
• Slit2 appeared to exert inhibitory as well as repulsive effects in the coculture assay [16].
• Furthermore, recombinant Slit2 can repel embryonic spinal motor axons in cell culture [17].
• To characterize these interactions in more detail, recombinant human Slit-2 protein and the N- and C-terminal portions generated by in vivo proteolytic processing were used in an enzyme-linked immunosorbent assay to measure the binding of a glypican-Fc fusion protein [18].
• Time-lapse videomicroscopy indicated that Slit2 reduced medulloblastoma invasion rate without affecting cell direction or proliferation [19].

References