期刊
CELL BIOCHEMISTRY AND FUNCTION
卷 31, 期 3, 页码 228-236出版社
WILEY
DOI: 10.1002/cbf.2876
关键词
Wnt; -catenin; TCF-4 pathway; high-mobility group A1 (HMGA1); colon cancer; oncogene; TCF-4 target gene; transcriptional activation
资金
- National Cancer Institute of the National Institutes for Health [1R15CA137520-01]
- National Center for Research Resources of the National Institutes for Health [5 P20 RR016461]
- National Institute of General Medical Sciences of the National Institutes for Health [8 P20 GM103499]
- National Science Foundation [MCB0542242]
High-mobility group A1 (HMGA1) encodes proteins that act as mediators in viral integration, modification of chromatin structure, neoplastic transformation and metastatic progression. Because HMGA1 is overexpressed in most cancers and has transcriptional relationships with several Wnt-responsive genes, we explored the involvement of HMGA1 in Wnt/-catenin/TCF-4 signalling. In adenomatous polyposis coli (APCMin/+) mice, we observed significant up-regulation of HMGA1 mRNA and protein in intestinal tumours when compared with normal intestinal mucosa. Conversely, restoration of Wnt signalling by the zinc induction of wild-type APC resulted in HMGA1 down-regulation in HT-29 cells. Because APC mutations are associated with mobilization of the -catenin/TCF-4 transcriptional complex and subsequent activation of downstream oncogenic targets, we analyzed the 5-flanking sequence of HMGA1 for putative TCF-4 binding elements. We identified two regions that specifically bind the -catenin/TCF-4 complex in vitro and in vivo, identifying HMGA1 as an immediate target of the -catenin/TCF-4 signalling pathway in colon cancer. Collectively, these findings strongly implicate Wnt/-catenin/TCF-4 signalling in regulating HMGA1 to further expand the extensive regulatory network affected by Wnt/-catenin/TCF-4 signalling. Copyright (c) 2012 John Wiley & Sons, Ltd.
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