HMGA1 Is Induced by Wnt/β-Catenin Pathway and Maintains Cell Proliferation in Gastric Cancer
HMGA1 Is Induced by Wnt/β-Catenin Pathway and Maintains Cell Proliferation in Gastric Cancer
复制标题
DOI：
10.2353/ajpath.2009.090069
复制
发表时间：
2009-10-01
影响因子：
6
通讯作者：
Nakao, Mitsuyoshi
中科院分区：
文献类型：
--
作者：
Akaboshi, Shin-ichi;Watanabe, Sugiko;Nakao, Mitsuyoshi
胃癌的发展与慢性炎症密切相关，并且Wnt/β-catenin信号通路在这种癌症的大多数情况下被激活。高迁移率族A（HMGA）蛋白是一种致癌染色质因子，不仅在未分化组织中表达，而且在各种肿瘤中也有表达。在这里，我们报告，HMGA 1是由Wnt/β-catenin途径诱导，并维持胃癌细胞的增殖。HMGA 1的特异性敲低导致细胞生长显著降低。β-连环蛋白或其下游c-myc的缺失降低了HMGA 1的表达，而Wnt 3a处理增加了HMGA 1和c-myc的转录。此外，Wnt 3a诱导的HMGA 1表达被c-myc敲除抑制，表明HMGA 1是Wnt/β-连环蛋白通路的下游靶点。约30%的胃癌组织中HMGA 1的表达增强与β-catenin在细胞核内的聚集共存。为了可视化HMGA 1在体内的表达，生成了表达内源性HMGA 1融合增强型绿色荧光蛋白的转基因小鼠，然后与K19-Wnt 1/C2 mE小鼠杂交，后者通过激活Wnt和前列腺素E2途径发生胃肿瘤。HMGA 1增强的绿色荧光蛋白的表达在腺胃的前胃、沿着上缘正常检测到，但其表达在癌性腺胃中也上调。这些数据表明，HMGA 1通过Wnt/β-连环蛋白途径参与增殖和胃肿瘤形成。(Am J Pathol 2009，175：1675-1685; DOI：10.2353/ajpath.2009.090069）
The development of stomach cancer is closely associated with chronic inflammation, and the Wnt/beta-catenin signaling pathway is activated in most cases of this cancer. High-mobility group A (HMGA) proteins are oncogenic chromatin factors that are primarily expressed not only in undifferentiated tissues but also in various tumors. Here we report that HMGA1 is induced by the Wnt/beta-catenin pathway and maintains proliferation of gastric cancer cells. Specific knockdown of HMGA1 resulted in marked reduction of cell growth. The loss of beta-catenin or its downstream c-myc decreased HMGA1 expression, whereas Wnt3a treatment increased HMGA1 and c-myc transcripts. Furthermore, Wnt3a-induced expression of HMGA1 was inhibited by c-myc knockdown, suggesting that HMGA1 is a downstream target of the Wnt/beta-catenin pathway. Enhanced expression of HMGA1 coexisted with the nuclear accumulation of beta-catenin in about 30% of gastric cancer tissues. To visualize the expression of HMGA1 in vivo, transgenic mice expressing endogenous; HMGA1 fused to enhanced green fluorescent protein were generated and then crossed with K19-Wnt1/C2mE mice, which develop gastric tumors through activation of both the Wnt and prostaglandin E2 pathways. Expression of HMGA1-enhanced green fluorescent protein was normally detected in the forestomach, along the upper border of the glandular stomach, but its expression was also up-regulated in cancerous glandular stomach. These data suggest that HMGA1 is involved in proliferation and gastric tumor formation via the Wnt/beta-catenin pathway. (Am J Pathol 2009, 175:1675-1685; DOI: 10.2353/ajpath.2009.090069)