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

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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 5 Pg. 3123-35 (Feb 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25605242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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