NOTCH Signaling and ATOH1 in Colorectal Cancers.
NOTCH Signaling and ATOH1 in Colorectal Cancers.
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DOI：
10.1007/s11888-011-0090-5
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发表时间：
2011-06
影响因子：
--
通讯作者：
Shroyer, Noah F
中科院分区：
文献类型：
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作者：
Kazanjian, Avedis;Shroyer, Noah F
Notch受体信号通路调节碱性螺旋-环-螺旋转录因子Atoh1(Math1/Hath1)的表达，从而决定细胞在肠道中的命运。在肠道干细胞的分化过程中，高水平的Notch活性指定了吸收性肠细胞/结肠细胞的分化，而高Atoh1活性指定了分泌型(高脚杯、肠内分泌和潘氏)细胞的分化。在结直肠癌中，Atoh1是一种肿瘤抑制因子，在大多数肿瘤中是沉默的，而Notch是致癌的，在人类肿瘤中通常非常活跃。在其他具有肠化生特征的胃肠道恶性肿瘤中，如食道癌和胃癌，Notch-Atoh1通路被激活。在保留激活Atoh1能力的癌症和癌前组织中，可以通过抑制Notch的活性(使用Notch靶向抗体或γ分泌酶的小分子抑制剂)来实现对这一途径的治疗性靶向。因此，靶向Notch-Atoh1通路是胃肠道肿瘤分化治疗的新途径。
The Notch receptor signaling pathway regulates expression of the basic helix-loop-helix transcription factor ATOH1 (Math1/Hath1) to determine cell fate in the intestine. In differentiating intestinal stem cells, high levels of Notch activity specify absorptive enterocyte/colonocyte differentiation, whereas high ATOH1 activity specifies secretory (goblet, enteroendocrine, and Paneth) cell differentiation. In colorectal cancer, ATOH1 is a tumor suppressor that is silenced in most tumors, while Notch is oncogenic and often highly active in human tumors. In other gastrointestinal malignancies with features of intestinal metaplasia, such as esophageal and gastric cancers, the Notch-ATOH1 pathway becomes activated. In cancers and preneoplastic tissues that retain the ability to activate ATOH1, therapeutic targeting of this pathway can be achieved by inhibiting Notch activity (with Notch-targeting antibodies or small-molecule inhibitors of γ-secretase). Thus, targeting the Notch-ATOH1 pathway represents a novel approach to differentiation therapy in gastrointestinal cancers.