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

// Qian-Qian Zhang 1,* , Da-lei Zhou 1,* , Yan Lei 1 , Li Zheng 1 , Sheng-Xia Chen 1 , Hong-Ju Gou 3 , Qu-Liang Gu 1 , Xiao-Dong He 1 , Tian Lan 1 , Cui-Ling Qi 1 , Jiang-Chao Li 1 , Yan-Qing Ding 3 , Liang Qiao 2 and Li-Jing Wang 1 1 Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou, China 2 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 2145, Australia 3 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China * These authors contributed equally to this work Correspondence: Li-Jing Wang, email: // Liang Qiao, email: // Keywords : Slit2/Robo1 signaling, intestinal tumors, Src, E-cadherin, Wnt/β-catenin Received : June 30, 2014 Accepted : December 12, 2014 Published : December 18, 2014 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 Apc Min/+ 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.