Slit-Robo signaling induces malignant transformation through Hakai-mediated E-cadherin degradation during colorectal epithelial cell carcinogenesis

被引：115

作者：

Zhou, Wei-Jie ^{[2
]}

Geng, Zhen H. ^{[1
]}

Chi, Shan ^{[2
]}

Zhang, Wenli ^{[3
,4
]}

Niu, Xiao-Feng ^{[2
]}

Lan, Shu-Jue ^{[2
]}

Ma, Li ^{[1
]}

Yang, Xuesong ^{[5
]}

Wang, Li-Jing ^{[6
]}

Ding, Yan-Qing ^{[3
,4
]}

Geng, Jian-Guo ^{[1
,6
]}

机构：

[1] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA

[2] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Mol Cell Biol Lab, Shanghai 200031, Peoples R China

[3] So Med Univ, Dept Pathol, Nanfang Hosp, Guangzhou 510515, Guangdong, Peoples R China

[4] So Med Univ, Sch Basic Med Sci, Guangzhou 510515, Guangdong, Peoples R China

[5] Jinan Univ, Coll Med, Minist Educ, Key Lab Regenerat Med, Guangzhou 510632, Guangdong, Peoples R China

[6] Guangdong Pharmaceut Univ, Vasc Biol Res Inst, Guangzhou 510006, Guangdong, Peoples R China

来源：

CELL RESEARCH | 2011年 / 21卷 / 04期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

colorectal carcinogenesis; E-cadherin; Hakai; Robo; Slit; BREAST-CANCER CELLS; FREQUENT EPIGENETIC INACTIVATION; REPULSIVE AXON GUIDANCE; MESENCHYMAL TRANSITION; BETA-CATENIN; ROUNDABOUT RECEPTOR; TUMOR ANGIOGENESIS; DOWN-REGULATION; IN-VIVO; ADHESION;

D O I：

10.1038/cr.2011.17

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The Slit family of guidance cues binds to Roundabout (Robo) receptors and modulates cell migration. We report here that ectopic expression of Slit2 and Robo1 or recombinant Slit2 treatment of Robo1-expressing colorectal epithelial carcinoma cells recruited an ubiquitin ligase Hakai for E-cadherin (E-cad) ubiquitination and lysosomal degradation, epithelial-mesenchymal transition (EMT), and tumor growth and liver metastasis, which were rescued by knockdown of Hakai. In contrast, knockdown of endogenous Robo1 or specific blockade of Slit2 binding to Robo1 prevented E-cad degradation and reversed EMT, resulting in diminished tumor growth and liver metastasis. Ectopic expression of Robo1 also triggered a malignant transformation in Slit2-positive human embryonic kidney 293 cells. Importantly, the expression of Slit2 and Robo1 was significantly associated with an increased metastatic risk and poorer overall survival in colorectal carcinoma patients. We conclude that engagement of Robo1 by Slit2 induces malignant transformation through Hakai-mediated E-cad ubiquitination and lysosomal degradation during colorectal epithelial cell carcinogenesis.

引用

页码：609 / 626

页数：18

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