Department of Internal Medicine III, Experimental and Translational Oncology, Johannes Gutenberg University, Obere Zahlbacherstr, 63, 55131 Mainz, Germany.
Mol Cancer. 2009 Sep 25;8:77. doi: 10.1186/1476-4598-8-77.
Colon cancer-associated MS4A12 is a novel colon-specific component of store-operated Ca2+ (SOC) entry sensitizing cells for epidermal growth factor (EGF)-mediated effects on proliferation and chemotaxis. In the present study, we investigated regulation of the MS4A12 promoter to understand the mechanisms responsible for strict transcriptional restriction of this gene to the colonic epithelial cell lineage. DNA-binding assays and luciferase reporter assays showed that MS4A12 promoter activity is governed by a single CDX homeobox transcription factor binding element. RNA interference (RNAi)-mediated silencing of intestine-specific transcription factors CDX1 and CDX2 and chromatin immunoprecipitation (ChIP) in LoVo and SW48 colon cancer cells revealed that MS4A12 transcript and protein expression is essentially dependent on the presence of endogenous CDX2. In summary, our findings provide a rationale for colon-specific expression of MS4A12. Moreover, this is the first report establishing CDX2 as transactivator of tumor growth-promoting gene expression in colon cancer, adding to untangle the complex and conflicting biological functions of CDX2 in colon cancer and supporting MS4A12 as important factor for normal colonic development as well as for the biology and treatment of colon cancer.
结肠癌相关的 MS4A12 是一种新型的、受细胞内钙库调控的钙通道（SOC）进入的结肠癌特异性组成部分，能够增强表皮生长因子（EGF）对细胞增殖和趋化性的作用。在本研究中，我们研究了 MS4A12 启动子的调控，以了解导致该基因严格转录局限于结肠上皮细胞谱系的机制。DNA 结合分析和荧光素酶报告基因分析表明，MS4A12 启动子活性受单个 CDX 同源盒转录因子结合元件调控。LoVo 和 SW48 结肠癌细胞中的 RNA 干扰（RNAi）介导的肠特异性转录因子 CDX1 和 CDX2 沉默以及染色质免疫沉淀（ChIP）实验显示，MS4A12 转录本和蛋白表达基本依赖于内源性 CDX2 的存在。总之，我们的研究结果为 MS4A12 的结肠特异性表达提供了依据。此外，这是首次报道 CDX2 作为结肠癌中促进肿瘤生长基因表达的转录激活因子，这增加了对 CDX2 在结肠癌中复杂且相互矛盾的生物学功能的理解，并支持 MS4A12 作为正常结肠发育以及结肠癌生物学和治疗的重要因素。
