STANDARD_NAME	TERAMOTO_OPN_TARGETS_CLUSTER_6
SYSTEMATIC_NAME	M1202
COLLECTION	C2:CGP
MSIGDB_URL	https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/TERAMOTO_OPN_TARGETS_CLUSTER_6
NAMESPACE	MOUSE_SEQ_ACCESSION
DESCRIPTION_BRIEF	Cluster 6:  genes exhibiting prolonged up-regulation (>72 h) after knockdown of OPN [GeneID=6696] by RNAi in the NIH3T3 cells (fibroblasts) transformed by activated HRAS [GeneID=3265].
DESCRIPTION_FULL	Activated forms of Ras family members are prevalent in many cancers where Ras mutants transduce signals essential for transformation, angiogenesis, invasion and metastasis. As a cancer progression model, we used NIH3T3 cells to explore the mechanism of Ras-induced tumorigenesis. Ras family mutants H-RasV12 and Rit79L strongly induced foci formation, while Rho family mutants RhoA-QL, Rac1-QL and Cdc42-QL were less effective. A comparison of downstream transcriptional targets of Ras and Rho family members using a 26 383 element cDNA microarray revealed that the osteopontin (OPN) gene exhibited the best correlation between magnitude of gene expression change and level of foci formation (r=0.96, P<0.001). In association with H-RasV12- and Rit79L-mediated transformation, foci secreted OPN protein and upregulated the OPN receptor CD44, suggesting the novel initiation of an aberrant OPN-CD44-Rac autocrine pathway. In support of this were the following observations. First, RGD-deficient OPN protein-binding activity was present in H-RasV12-transformed cells but not in control cells, and binding activity was inhibited by the CD44 blocking antibody. Second, foci formation, cell invasion and Rac activity were induced by H-RasV12 and inhibited by the CD44 blocking antibody. Third, foci formation by H-RasV12 was substantially reduced by a short interfering RNA (siRNA) specifically targeting OPN expression for knockdown. Fourth, H-RasV12-mediated transformation was not blocked by the GRGDS peptide, suggesting that OPN effects were not mediated by the integrins. Lastly, OPN knockdown affected the downstream expression of 160 '2nd tier' genes, and at least a subset of these genes appears to be involved in transformation. Indeed, four genes were selected for knockdown, each resulting in a disruption of foci formation and/or invasion. These results underscore the role of aberrant autocrine signaling and transcriptional networking during tumorigenesis.
PMID	15516973
GEOID	
AUTHORS	Teramoto H,Castellone MD,Malek RL,Letwin N,Frank B,Gutkind JS,Lee NH
CONTRIBUTOR	Arthur Liberzon
CONTRIBUTOR_ORG	MSigDB Team
EXACT_SOURCE	Suppl. Data: Cluster 6
FILTERED_BY_SIMILARITY	
EXTERNAL_NAMES_FOR_SIMILAR_TERMS	
EXTERNAL_DETAILS_URL	
SOURCE_MEMBERS	AI181841,AI835650,AI838653,AI839977,AI840024,AI845456,AI845602,AI845927,AI846640,AI847823,AI850900,AI851745,AI852961,AI853657,AU017967,AU018218,AU040471,AU042755,AU044656,AW411866,AW550633,AW555055,AW556282,AW557755,AW557957,AW558946,AW558948,AW743042,BE380320,C86882
GENE_SYMBOLS	SOAT1,TMEM107,CCDC80,NDRG2,APOD,ACTN4,PDGFRB,DAND5,KCTD20,ADAMTS7,,SPARCL1,SLIT1,RITA1,MMP7,,BLOC1S1,PIH1D1,CCDC3,PSME1,OLFML3,,GFUS,TSPAN9,ZDHHC2,PPP5C,ELMO2,ACACB,SERPINF1,
FOUNDER_NAMES