STANDARD_NAME SASAI_TARGETS_OF_CXCR6_AND_PTCH1_UP SYSTEMATIC_NAME M10694 COLLECTION C2:CGP MSIGDB_URL https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/SASAI_TARGETS_OF_CXCR6_AND_PTCH1_UP NAMESPACE AFFY_Mouse430 DESCRIPTION_BRIEF Up-regulated genes in medulloblastoma tumors from heterozygotic CXCR6 [GeneID=10663] knockout mice compared to those from PTCH1 [GeneID=5727] heterozygotic knockout mice. DESCRIPTION_FULL The sonic hedgehog (Shh) pathway is activated in approximately 30% of human medulloblastoma resulting in increased expression of downstream target genes. In about half of these cases, this has been shown to be a consequence of mutations in regulatory genes within the pathway, including Ptc1, Smo, and Sufu. However, for some tumors, no mutations have been detected in known pathway genes. This suggests that either mutations in other genes promote tumorigenesis or that epigenetic alterations increase pathway activity in these tumors. Here, we report that 3% to 4% of mice lacking either one or both functional copies of Cxcr6 develop medulloblastoma. Although CXCR6 is not known to be involved in Shh signaling, tumors derived from Cxcr6 mutant mice expressed Shh pathway target genes including Gli1, Gli2, Ptc2, and Sfrp1, indicating elevated pathway activity. Interestingly, the level of Ptc1 expression was decreased in tumor cells although two normal copies of Ptc1 were retained. This implies that reduced CXCR6 function leads to suppression of Ptc1 thereby increasing Smoothened function and promoting tumorigenesis. We used a direct transplant model to test the sensitivity of medulloblastoma arising in Cxcr6 mutant mice to a small-molecule inhibitor of Smoothened (HhAntag). We found that transplanted tumors were dramatically inhibited in mice treated for only 4 days with HhAntag. These findings suggest that HhAntag may be effective against tumors lacking mutations in known Shh pathway genes. PMID 17413002 GEOID GSE7212 AUTHORS Sasai K,Romer JT,Kimura H,Eberhart DE,Rice DS,Curran T CONTRIBUTOR Jessica Robertson CONTRIBUTOR_ORG MSigDB Team EXACT_SOURCE Table 2S: log-ratio > 0 FILTERED_BY_SIMILARITY EXTERNAL_NAMES_FOR_SIMILAR_TERMS EXTERNAL_DETAILS_URL SOURCE_MEMBERS 1416629_at,1418876_at,1421958_at,1425339_at,1425469_a_at,1425926_a_at,1426906_at,1427262_at,1427820_at,1428578_s_at,1434340_at,1435455_at,1436094_at,1436936_s_at,1447096_at,1449526_a_at,1451580_a_at,1452231_x_at,1456108_x_at GENE_SYMBOLS SLC1A5,FOXD1,L1CAM,PLCB4,,OTX2,IFI16,XIST,,PPFIA4,UQCR10,IFFO2,VGF,XIST,,GDPD3,TTR,IFI16,RNF112 FOUNDER_NAMES