共查询到3条相似文献,搜索用时 0 毫秒
1.
2.
Tumor necrosis factor alpha blockade restores growth hormone signaling in murine colitis 总被引:2,自引:0,他引:2
DiFedele LM He J Bonkowski EL Han X Held MA Bohan A Menon RK Denson LA 《Gastroenterology》2005,128(5):1278-1291
3.
The metastasis-associated gene S100A4 is a novel target of beta-catenin/T-cell factor signaling in colon cancer 总被引:1,自引:0,他引:1
Stein U Arlt F Walther W Smith J Waldman T Harris ED Mertins SD Heizmann CW Allard D Birchmeier W Schlag PM Shoemaker RH 《Gastroenterology》2006,131(5):1486-1500
BACKGROUND & AIMS: Activation of the Wnt/beta-catenin pathway is frequently observed in colorectal cancers. Our aim was to elucidate the impact of gain-of-function beta-catenin on the metastasis-associated gene S100A4 in human colon cancer cell lines and tumors. METHODS: We analyzed cell lines heterozygous for gain-of-function and wild-type beta-catenin, and variants homozygous for gain- or loss-of-function mutation in beta-catenin, for S100A4 expression, cell motility, and in vivo metastasis. beta-catenin-mediated S100A4 promoter activation was tested by reporter assays. For human colon carcinomas, S100A4 expression, beta-catenin genotype, and metachronous metastasis were correlated. RESULTS: We identified S100A4 as the most regulated gene by gain-of-function beta-catenin using a 10K microarray. Cell lines with gain-of-function beta-catenin expressed up to 60-fold elevated S100A4 levels, displayed strongly increased migration and invasion in vitro, and induced metastasis in mice. S100A4 small interfering RNA, beta-catenin small interfering RNA, or dominant negative T-cell factor (TCF) knocked down S100A4 and blocked biological effects. S100A4 complementary DNA transfection increased migration and invasion. We identified a TCF binding site within the S100A4 promoter and demonstrated the direct binding of heterodimeric beta-catenin/TCF complexes. Reporter assays confirmed the beta-catenin-induced S100A4 promoter activity. Furthermore, S100A4 mRNA expression was increased in primary colon cancers, which later developed distant metastases, compared to non-metastasizing tumors. Colon tumors heterozygous for gain-of-function beta-catenin showed concomitant nuclear beta-catenin localization, high S100A4 expression, and metastases. CONCLUSIONS: S100A4 is a direct beta-catenin/TCF target, induces migration and invasion in vitro and metastasis in vivo, and has value for prognosis of metastasis formation in colon cancer patients. 相似文献