STANDARD_NAME TERAMOTO_OPN_TARGETS_CLUSTER_1 SYSTEMATIC_NAME M1197 COLLECTION C2:CGP MSIGDB_URL https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/TERAMOTO_OPN_TARGETS_CLUSTER_1 NAMESPACE MOUSE_SEQ_ACCESSION DESCRIPTION_BRIEF Cluster 1: genes whose up-regulation peaked one day 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 1 FILTERED_BY_SIMILARITY EXTERNAL_NAMES_FOR_SIMILAR_TERMS EXTERNAL_DETAILS_URL SOURCE_MEMBERS AI837750,AI839337,AI840465,AI841616,AI845765,AI848986,AI849200,AI850189,AI853671,AI854755,AU023262,AU041577,AU041758,AU044846,AW542416,AW553554,AW553664,AW555717,AW557657,BE307648,BE373645,C77469,C80816,C87989 GENE_SYMBOLS IDH1,,INSIG1,,SC5D,,,TMEM50B,GFOD2,ACTL6B,DCLK3,,PLCD3,,FMR1NB,BNIP3,,,,HMGCR,ERBB3,LSS,,TFRC FOUNDER_NAMES