Integrin α1β1 expression is controlled by c-MYC in colorectal cancer cells.
Integrin α1β1 expression is controlled by c-MYC in colorectal cancer cells.
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DOI：
10.1038/onc.2015.231
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发表时间：
2016-03-31
期刊：
影响因子：
8
通讯作者：
Beaulieu JF
中科院分区：
文献类型：
--
作者：
Boudjadi S;Carrier JC;Groulx JF;Beaulieu JF
α1β1胶原受体仅存在于少数上皮细胞类型中。在肠中，它在增殖的隐窝细胞中特异性表达。据报道，这种整合素参与多种癌症，介导Ras/ERK增殖途径的下游激活。我们最近发现整合素α1β1存在于三分之二的结肠腺癌中，但ITGA1表达调控的机制尚不清楚。DNA甲基化参与巨核细胞分化过程中ITGA1的抑制，但不是结直肠癌细胞中ITGA1调控的机制。我们对ITGA1启动子的计算机分析揭示了MYC的两个应答元件，MYC是一种已知的调节癌细胞增殖、侵袭和迁移的致癌因子。原位分析中，MYC和ITGA1的表达均定位于正常结肠的下隐窝，在分析的65例结直肠癌中，有72%的MYC和ITGA1表达相关。在HT29、T84和SW480细胞中，MYC药物抑制或下调短发夹RNA的表达导致ITGA1在转录物和蛋白水平上的表达降低。染色质免疫沉淀试验显示，MYC与ITGA1近端启动子的染色质区域结合，而MYC过表达增强了ITGA1启动子的活性，这种活性在MAD共转染或反应元件破坏时降低。我们认为MYC是控制ITGA1表达的关键调节因子。
The α1β1 collagen receptor is only present in a few epithelial cell types. In the intestine, it is specifically expressed in proliferating crypt cells. This integrin has been reported to be involved in various cancers where it mediates the downstream activation of the Ras/ERK proliferative pathway. We have recently shown that integrin α1β1 is present in two-thirds of colon adenocarcinomas, but the mechanism by which ITGA1 expression is regulated is not known. DNA methylation, involved in ITGA1 repression during megakaryocyte differentiation, is not the mechanism of ITGA1 regulation in colorectal cancer cells. Our in silico analysis of the ITGA1 promoter revealed two response elements for MYC, an oncogenic factor known to regulate cancer cell proliferation, invasion and migration. In situ, the expressions of both MYC and ITGA1 are localized in the lower crypt of the normal colon and correlate in 72% of the 65 analyzed colorectal cancers. MYC pharmacological inhibition or downregulation of expression with short hairpin RNA in HT29, T84 and SW480 cells resulted in reduced ITGA1 expression at both the transcript and protein levels. Chromatin immunoprecipitation assays revealed that MYC was bound to the chromatin region of the ITGA1 proximal promoter, whereas MYC overexpression enhanced ITGA1 promoter activity that was reduced with MAD co-transfection or by the disruption of the response elements. We concluded that MYC is a key regulating factor for the control of ITGA1 expression.