title: Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3β/β-catenin pathways.
abstract: Metastasis is a major cause of death in human colorectal cancer patients. However, the contribution of chemokines in the tumor microenvironment to tumor metastasis is not fully understood.
  
  
  
  Herein, we examinined several chemokines in colorectal cancer patients using chemokine ELISA array. Immunohistochemistry was used to detect expression of CXCL5 in colorectal cancer patients tissues. Human HCT116 and SW480 cell lines stably transfected with CXCL5, shCXCL5 and shCXCR2 lentivirus plasmids were used in our in vitro study. Immunoblot, immunofluorescence and transwell assay were used to examine the molecular biology and morphological changes in these cells. In addition, we used nude mice to detect the influence of CXCL5 on tumor metastasis in vivo.
  
  
  
  We found that CXCL5 was overexpressed in tumor tissues and associated with advanced tumor stage as well as poor prognosis in colorectal cancer patients. We also demonstrated that CXCL5 was primarily expressed in the tumor cell cytoplasm and cell membranes, which may indicate that the CXCL5 was predominantly produced by cancer epithelial cells instead of fibroblasts in the tumor mesenchyme. Additionally, overexpression of CXCL5 enhanced the migration and invasion of colorectal cancer cells by inducing the epithelial-mesenchymal transition (EMT) through activation of the ERK/Elk-1/Snail pathway and the AKT/GSK3β/β-catenin pathway in a CXCR2-dependent manner. The silencing of Snail and β-catenin attenuated CXCL5/CXCR2-enhanced cell migration and invasion in vitro. The elevated expression of CXCL5 can also potentiate the metastasis of colorectal cancer cells to the liver in vivo in nude mice intrasplenic injection model.
  
  
  
  In conclusion, our findings support CXCL5 as a promoter of colorectal cancer metastasis and a predictor of poor clinical outcomes in colorectal cancer patients.
authors.affiliation: Shanghai Minimally Invasive Surgery Center, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.|Shanghai Institute of Digestive Surgery, Shanghai, People's Republic of China.|Department of General, Visceral, Transplantation, and Vascular Thoracic Surgery, Hospital of University of LMU Munich, Munich, Germany.
authors.forename: Jingkun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Shanghai Minimally Invasive Surgery Center, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.|Shanghai Institute of Digestive Surgery, Shanghai, People's Republic of China.
authors.forename: Baochi
authors.initials: B
authors.lastname: Ou
authors.affiliation: Department of thoracic surgery, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Dingpei
authors.initials: D
authors.lastname: Han
authors.affiliation: Shanghai Minimally Invasive Surgery Center, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Puxiongzhi
authors.initials: P
authors.lastname: Wang
authors.affiliation: Shanghai Minimally Invasive Surgery Center, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China. angela_zyp@126.com.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zong
authors.affiliation: Shanghai Minimally Invasive Surgery Center, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.|Shanghai Institute of Digestive Surgery, Shanghai, People's Republic of China.
authors.forename: Congcong
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Shanghai Minimally Invasive Surgery Center, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Liu
authors.affiliation: Shanghai Minimally Invasive Surgery Center, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Minhua
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Shanghai Minimally Invasive Surgery Center, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of General, Visceral, Transplantation, and Vascular Thoracic Surgery, Hospital of University of LMU Munich, Munich, Germany. daladaladi@gmail.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.affiliation: Shanghai Minimally Invasive Surgery Center, Ruijin hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China. luaiguo1965@163.com.|Shanghai Institute of Digestive Surgery, Shanghai, People's Republic of China. luaiguo1965@163.com.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Lu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D054365:Chemokine CXCL5 / Q000235:genetics / Q000378:metabolism*; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D008954:Models, Biological; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: D054365:Chemokine CXCL5; D023063:Receptors, Interleukin-8B; D000071250:Snail Family Transcription Factors; D051176:beta Catenin; D050807:ets-Domain Protein Elk-1; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: CXCL5; Colorectal cancer; EMT; Snail; β-catenin