Slit2/Robo1 signaling promotes intestinal tumorigenesis through Src-mediated activation of the Wnt/β-catenin pathway

Qian-Qian Zhang; Da-Lei Zhou; Yan Lei; Li Zheng; Sheng-Xia Chen; Hong-Ju Gou; Qu-Liang Gu; Xiao-Dong He; Tian Lan; Cui-Ling Qi; Jiang-Chao Li; Yan-Qing Ding; Liang Qiao; Li-Jing Wang

doi:10.18632/oncotarget.3060

Slit2/Robo1 signaling promotes intestinal tumorigenesis through Src-mediated activation of the Wnt/β-catenin pathway

Oncotarget. 2015 Feb 20;6(5):3123-35. doi: 10.18632/oncotarget.3060.

Authors

Affiliations

¹ Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China.
² Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
³ Storr Liver Center, Westmead Millennium Institute for Medical Research, The Western Clinical School of the Faculty of Medicine, The University of Sydney at the Westmead Hospital, Westmead, NSW, Australia.

Abstract

Slit2 is often overexpressed in cancers. Slit2 is a secreted protein that binds to Roundabout (Robo) receptors to regulate cell growth and migration. Here, we employed several complementary mouse models of intestinal cancers, including the Slit2 transgenic mice, the ApcMin/+ spontaneous intestinal adenoma mouse model, and the DMH/DSS-induced colorectal carcinoma model to clarify function of Slit2/Robo1 signaling in intestinal tumorigenesis. We showed that Slit2 and Robo1 are overexpressed in intestinal tumors and may contribute to tumor generation. The Slit2/Robo1 signaling can induce precancerous lesions of the intestine and tumor progression. Ectopic expression of Slit2 activated Slit2/Robo1 signaling and promoted tumorigenesis and tumor growth. This was mediated in part through activation of the Src signaling, which then down-regulated E-cadherin, thereby activating Wnt/β-catenin signaling. Thus, Slit2/Robo1 signaling is oncogenic in intestinal tumorigenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenoma / enzymology*
Adenoma / genetics
Adenoma / pathology
Animals
Carcinoma / enzymology*
Carcinoma / genetics
Carcinoma / pathology
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Colorectal Neoplasms / enzymology*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / pathology
Disease Models, Animal
Disease Progression
Female
Genes, APC
HCT116 Cells
Humans
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
Intestinal Mucosa / enzymology*
Intestinal Mucosa / pathology
Male
Mice, Inbred C57BL
Mice, Transgenic
Middle Aged
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
RNA Interference
Receptors, Immunologic / genetics
Receptors, Immunologic / metabolism*
Roundabout Proteins
Transfection
Tumor Burden
Wnt Signaling Pathway*
beta Catenin / metabolism*
src-Family Kinases / metabolism*

Substances

CTNNB1 protein, human
CTNNB1 protein, mouse
Intercellular Signaling Peptides and Proteins
Nerve Tissue Proteins
Receptors, Immunologic
beta Catenin
src-Family Kinases
Slit homolog 2 protein