Achaete scute-like 2 suppresses CDX2 expression and inhibits intestinal neoplastic epithelial cell differentiation.
Achaete scute-like 2 suppresses CDX2 expression and inhibits intestinal neoplastic epithelial cell differentiation.
复制标题
Achaete scute-like 2抑制CDX2表达并抑制肠肿瘤上皮细胞分化
DOI：
10.18632/oncotarget.5206
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发表时间：
2015-10-13
期刊：
影响因子：
--
通讯作者：
Wang R
中科院分区：
文献类型：
--
作者：
Shang Y;Pan Q;Chen L;Ye J;Zhong X;Li X;Meng L;Guo J;Tian Y;He Y;Chen W;Peng Z;Wang R
Achaete scute-like 2 (Ascl2) 在结直肠癌 (CRC) 细胞分化中的作用尚不清楚。 LS174T、HT-29 和 Caco-2 细胞具有高 Ascl2 表达，而 Lovo 和 SW480 细胞具有低 Ascl2 表达。 Ascl2 敲低的 LS174T 和 HT-29 细胞用尾型同源框 2 (CDX2) 启动子构建体转染，并用于荧光素酶测定和染色质免疫沉淀 (ChIP) 测定。 Ascl2 敲除促进了 CRC 细胞分化为杯状细胞表型，这一点通过 MUC2、TFF3 和 CDX2 表达增加来确定。 Ascl2 敲低通过 Ascl2 直接结合 CDX2 启动子的近端 E-box 的转录机制激活 CDX2 表达。 Lovo 和 SW480 细胞中 Ascl2 的过度表达抑制了杯状细胞表型，这一点通过 CDX2 和 MUC2 表达的减少来确定。在 CRC 癌样本中观察到 Ascl2 和 CDX2、Ascl2 和 MUC2 mRNA 水平以及 Ascl2 和 CDX2 蛋白水平之间呈负相关。这项研究证明了 Ascl2 对 CDX2 的抑制，并强调了 Ascl2 在 CRC 细胞分化中的作用。这些发现表明 Ascl2/CDX2 轴可能作为结直肠癌的潜在治疗靶点。
The role of Achaete scute-like 2 (Ascl2) in colorectal cancer (CRC) cell differentiation is unknown. LS174T, HT-29 and Caco-2 cells have high Ascl2 expression, while Lovo and SW480 cells have low Ascl2 expression. LS174T and HT-29 cells with Ascl2 knockdown were transfected with caudal type homeobox 2 (CDX2) promoter constructs and used for luciferase assays and chromatin immunoprecipitation (ChIP) assays. Ascl2 knockdown promoted differentiation of CRC cells into a goblet cell phenotype, as determined by increased expression of MUC2, TFF3, and CDX2. Ascl2 knockdown activated CDX2 expression through a transcriptional mechanism via direct binding of Ascl2 to the proximal E-box of the CDX2 promoter. Ascl2 over-expression in Lovo and SW480 cells inhibited a goblet cell phenotype, as determined by reduced CDX2 and MUC2 expression. Inverse correlations between Ascl2 and CDX2, and Ascl2 and MUC2 mRNA levels, as well as Ascl2 and CDX2 protein levels were observed in CRC cancerous samples. This study demonstrates CDX2 repression by Ascl2 and highlights a role for Ascl2 in CRC cell differentiation. These findings suggest that the Ascl2/CDX2 axis may serve as a potential therapeutic target in colorectal cancer.