IGFBP3, a Transcriptional Target of Homeobox D10, Is Correlated with the Prognosis of Gastric Cancer
IGFBP3, a Transcriptional Target of Homeobox D10, Is Correlated with the Prognosis of Gastric Cancer
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同源盒 D10 的转录靶标 IGFBP3 与胃癌的预后相关
DOI：
10.1371/journal.pone.0081423
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发表时间：
2013-12-27
期刊：
影响因子：
3.7
通讯作者：
Chen, Shujie
中科院分区：
文献类型：
--
作者：
Xue, Meng;Fang, Yanfei;Chen, Shujie
同源盒D10(HoxD10)在胚胎细胞分化和乳腺癌进展中起重要作用。我们先前的报道表明，胰岛素样生长因子结合蛋白-3(IGFBP3)在胃癌细胞中受HoxD10的调控，然而，IGFBP3在胃癌中的功能作用和潜在机制尚不清楚。在此，我们发现HoxD10异位表达后，IGFBP3的表达上调。染色质免疫沉淀分析表明，HoxD10与IGFBP3启动子的三个潜在区域结合。外源HoxD10可显著增强胃癌细胞中含有这些结合区域的荧光素酶报告基因的活性。进一步的数据表明，所有这些结合位点都含有HOX结合元件“TTAT”。免疫组织化学染色结果显示，86例胃腺癌组织中IGFBP3的表达明显低于癌旁组织(p<；0.001)。有淋巴结转移的胃癌组织中IGFBP3的表达明显低于无淋巴结转移的胃癌组织(p=0.045)。IGFBP3高表达患者的5年总生存率较好(p=0.011)。IGFBP3基因敲除促进了胃癌细胞的迁移和侵袭，并诱导了MMP14、uPA和uPAR等侵袭因子的表达。因此，我们的数据提示，HoxD10靶向基因IGFBP3可能抑制胃癌细胞的侵袭，有利于胃癌患者的生存。
Homeobox D10 (HoxD10) plays important roles in the differentiation of embryonic cells and progression of breast cancer. Our previous report revealed that insulin-like growth factor binding protein-3 (IGFBP3) was regulated by HoxD10 in gastric cancer cells; however, the functional roles and underlying mechanisms of IGFBP3 in gastric cancer remain unclear. Here, we found that the expression of IGFBP3 were upregulated after ectopic expression of HoxD10 in gastric cancer cells. Chromatin immunoprecipitation assay showed that HoxD10 bound to three potential regions of IGFBP3 promoter. Exogenous HoxD10 significantly enhanced the activity of luciferase reporter containing these binding regions in gastric cancer cells. Further data showed that all of these binding sites had Hox binding element “TTAT”. Immunohistochemical staining results revealed that IGFBP3 expression was significantly downregulated in 86 gastric adenocarcinomas tissues relative to their adjacent non-cancerous tissues (p<0.001). Moreover, IGFBP3 expression was significantly lower in gastric tumor with lymph node metastasis compared with that without lymph node metastasis (p=0.045). Patients with high expression level of IGFBP3 showed favorable 5 year overall survival (p=0.011). Knockdown of IGFBP3 accelerated gastric cancer cell migration and invasion and induced the expression of invasive factors including MMP14, uPA and uPAR. Thus, our data suggest that HoxD10-targeted gene IGFBP3 may suppress gastric cancer cell invasion and favors the survival of gastric cancer patients.