FOXD3 is a tumor suppressor of colon cancer by inhibiting EGFR-Ras-Raf-MEK-ERK signal pathway

// Kun Li 1, 2, 3, * , Qunfeng Guo 4, * , Jun Yang 4, * , Hui Chen 3 , Kewen Hu 3 , Juan Zhao 1, 2 , Shunxin Zheng 1, 2 , Xiufeng Pang 3 , Sufang Zhou 1, 2 , Yongyan Dang 3 , Lei Li 3 1 Department of Biochemistry and Molecular Biology, Guangxi Medical University, Nanning, Guangxi, China 2 National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Guangxi Medical University, Nanning, Guangxi, China 3 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, China 4 Department of Orthopedics, Changzheng Hospital, The Second Military Medical University, Shanghai, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Yongyan Dang, email: yydang@bio.ecnu.edu.cn Xiufeng Pang, email: xfpang@bio.ecnu.edu.cn Sufang Zhou, email: zsf200000@163.com Lei Li, email: lllkzj@163.com Keywords: FOXD3, colon cancer, EGFR, Ras/Raf/MEK/ERK signal pathway Received: June 03, 2016     Accepted: November 12, 2016     Published: December 03, 2016 ABSTRACT Forkhead box D3 (FOXD3), as a transcriptional repressor, is well known to be involved in the regulation of development. Although FoxD3 is associated with several cancers, its role in colon cancer and the underlying mechanism are still unclear. Here, we first showed that FOXD3 knockdown dramatically increased the proliferation of human colon cancer cells, enhanced cell invasive ability and inhibited cell apoptosis. In vivo xenograft studies confirmed that the FOXD3 -knockdown cells were more tumorigenic than the controls. Silencing FOXD3 markedly activated EGFR/Ras/Raf/MEK/ERK pathway in human colon cancer cells. In addition, blocking EGFR effectively decreased the activity of MAPK induced by FOXD3 knockdown. In human cancer tissue, the expression of FOXD3 was reduced, however, the EGFR/Ras/Raf/MEK/ERK pathway was activated. Our study indicates that FOXD3 may play a protective role in human colon formation by regulating EGFR/Ras/Raf/MEK/ERK signal pathway. It is proposed that FOXD3 may have potential as a new therapeutic target in human colon cancer treatment.