Department of Chemistry, Physics, and Geology, Winthrop University, Rock Hill, SC 29733, USA.
Cell Biochem Funct. 2013 Apr;31(3):228-36. doi: 10.1002/cbf.2876. Epub 2012 Sep 7.
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/β-catenin/TCF-4 signalling. In adenomatous polyposis coli (APC(Min/+)) 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 β-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 β-catenin/TCF-4 complex in vitro and in vivo, identifying HMGA1 as an immediate target of the β-catenin/TCF-4 signalling pathway in colon cancer. Collectively, these findings strongly implicate Wnt/β-catenin/TCF-4 signalling in regulating HMGA1 to further expand the extensive regulatory network affected by Wnt/β-catenin/TCF-4 signalling.
高迁移率族蛋白 A1（HMGA1）编码的蛋白质作为病毒整合、染色质结构修饰、肿瘤转化和转移进展的介质。由于 HMGA1 在大多数癌症中过度表达，并且与几个 Wnt 反应基因具有转录关系，我们探讨了 HMGA1 在 Wnt/β-catenin/TCF-4 信号通路中的参与。在腺瘤性结肠息肉病（APC(Min/+)）小鼠中，与正常肠黏膜相比，我们观察到肠道肿瘤中 HMGA1 mRNA 和蛋白的显著上调。相反，野生型 APC 的锌诱导恢复 Wnt 信号导致 HT-29 细胞中 HMGA1 的下调。由于 APC 突变与β-catenin/TCF-4 转录复合物的动员以及随后下游致癌靶标的激活有关，我们分析了 HMGA1 的 5'-侧翼序列以寻找可能的 TCF-4 结合元件。我们鉴定了两个区域，它们可以在体外和体内特异性结合β-catenin/TCF-4 复合物，鉴定 HMGA1 为结肠癌中β-catenin/TCF-4 信号通路的直接靶标。总之，这些发现强烈表明 Wnt/β-catenin/TCF-4 信号通路在调节 HMGA1 以进一步扩大受 Wnt/β-catenin/TCF-4 信号通路影响的广泛调节网络方面具有重要作用。
