NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer.
NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer.
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DOI：
10.1158/0008-5472.can-09-2557
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发表时间：
2010-02-15
期刊：
影响因子：
11.2
通讯作者：
Lipkin SM
中科院分区：
文献类型：
--
作者：
Sikandar SS;Pate KT;Anderson S;Dizon D;Edwards RA;Waterman ML;Lipkin SM
NOTCH信号传导在肠上皮细胞谱系特化和结直肠腺瘤和结直肠癌（CRC）的起始中发挥关键功能。由于NOTCH信号传导在几种类型的恶性肿瘤中的癌症起始细胞的维持和自我更新中也起重要作用，因此我们研究了NOTCH信号传导在结肠癌起始细胞（CCIC）中的作用。CCIC形成的肿瘤保持了它们所来源的原发性CRC的许多特性，例如腺体组织、细胞极性、间隙连接和特征性CRC分子标记物的表达。此外，CCIC还具有自我更新的特性。在这里，我们表明，NOTCH信号是10-30倍高CCIC相比，常用的结肠癌细胞系。使用小分子抑制和shRNA敲除，我们证明NOTCH通过抑制p27和ATOH 1来防止CCIC凋亡。NOTCH还在CCIC自我更新的内在维持和分泌细胞谱系分化基因如MUC 2的抑制中起关键作用。我们的研究描述了一种新的人类细胞系统来研究CRC肿瘤起始中的NOTCH信号传导，并表明抑制NOTCH信号传导可能是改善CRC化学预防和化疗的重要机制。
NOTCH signaling fulfills critical functions in intestinal epithelial cell lineage specification and the initiation of colorectal adenomas and colorectal cancers (CRCs). Because NOTCH signaling also plays important roles in the maintenance and self-renewal of cancer initiating cells in several types of malignancies, we studied the role of NOTCH signaling in colon cancer initiating cells (CCIC). CCIC form tumors that maintain many properties of the primary CRCs from which they were derived, such as glandular organization, cell polarity, gap junctions, and expression of characteristic CRC molecular markers. Furthermore, CCIC have the property of self-renewal. Here, we show that NOTCH signaling is 10-30 fold higher in CCIC compared to commonly used colon cancer cell lines. Using small molecule inhibition and shRNA knockdown, we demonstrate that NOTCH prevents CCIC apoptosis through repression of p27 and ATOH1. NOTCH also plays critical roles in the intrinsic maintenance of CCIC self-renewal, and the repression of secretory cell lineage differentiation genes such as MUC2. Our studies describe a novel human cell system to study NOTCH signaling in CRC tumor initiation and suggest inhibition of NOTCH signaling is likely to be an important mechanism to improve CRC chemoprevention and chemotherapy.