title: CCL20 and CXCL8 synergize to promote progression and poor survival outcome in patients with colorectal cancer by collaborative induction of the epithelial-mesenchymal transition.
abstract: Liver metastases represent the major cause of death in patients with colorectal cancer (CRC). Recent studies have suggested that the chemotactic responses of tumor cells are necessary for metastatic spread to the liver, and CCL20 and CXCL8 have a strong association with CRC metastasis. The aim of our study was to identify the mechanisms by which CCL20 and CXCL8 synergize to promote metastatic progression and evaluated their potential as prognostic markers for CRC patients. The abilities of CCL20 and CXCL8 to promote CRC cell progression and epithelial-mesenchymal transition(EMT)phenotype were analyzed in vitro. Possible signaling pathways were investigated with specific pathway inhibitors and small interfering RNA (siRNA). 213 Patients with CRC who underwent surgery were enrolled for analysis of CCL20, CXCL8 and E-cadherin expressions in tumor tissues. Prognostic factors were then identified. CCL20 or CXCL8 alone was not sufficient to induce complete EMT in CRC cells, but both of them could coordinately induce EMT-like phenotype that was required to maintain CRC cell proliferation, migration and invasion. PI3K/AKT-ERK1/2 pathway crosstalk was demonstrated to be responsible for this process. Coexpression of CCL20 and CXCL8 was negatively correlated with E-cadherin expression in human CRC tissues. CRC patients with coexpression of CCL20 and CXCL8 were more likely to develop liver metastases and both coexpression was an independent high-risk factor for a most poor prognosis. CCL20 and CXCL8 synergize to promote CRC metastatic progression by coordinated induction of EMT via PI3K/AKT-ERK1/2 signaling axis. Detection of both coexpressions can be used to predict clinical outcomes in CRC patients.
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, PR China; Colorectal Cancer Clinical Research Center, Third Affiliated Hospital, Kunming Medical University, 650118 Kunming, Yunnan, PR China.
authors.forename: Xian-Shuo
authors.initials: XS
authors.lastname: Cheng
authors.affiliation: Colorectal Cancer Clinical Research Center, Third Affiliated Hospital, Kunming Medical University, 650118 Kunming, Yunnan, PR China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Li
authors.affiliation: Colorectal Cancer Clinical Research Center, Third Affiliated Hospital, Kunming Medical University, 650118 Kunming, Yunnan, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tan
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.affiliation: Colorectal Cancer Clinical Research Center, Third Affiliated Hospital, Kunming Medical University, 650118 Kunming, Yunnan, PR China.
authors.forename: You-Chuan
authors.initials: YC
authors.lastname: Xiao
authors.affiliation: Colorectal Cancer Clinical Research Center, Third Affiliated Hospital, Kunming Medical University, 650118 Kunming, Yunnan, PR China.
authors.forename: Xing-Bao
authors.initials: XB
authors.lastname: Fang
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, PR China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: Colorectal Cancer Clinical Research Center, Third Affiliated Hospital, Kunming Medical University, 650118 Kunming, Yunnan, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Colorectal Cancer Clinical Research Center, Third Affiliated Hospital, Kunming Medical University, 650118 Kunming, Yunnan, PR China.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Dong
authors.affiliation: Colorectal Cancer Clinical Research Center, Third Affiliated Hospital, Kunming Medical University, 650118 Kunming, Yunnan, PR China.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, PR China.
authors.forename: Hai-hua
authors.initials: HH
authors.lastname: Qian
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, PR China. Electronic address: yinzfk@aliyun.com.
authors.forename: Zheng-Feng
authors.initials: ZF
authors.lastname: Yin
authors.affiliation: Colorectal Cancer Clinical Research Center, Third Affiliated Hospital, Kunming Medical University, 650118 Kunming, Yunnan, PR China. Electronic address: yzblbab@vip.sina.com.
authors.forename: Zhi-Bin
authors.initials: ZB
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D015703:Antigens, CD; D018938:Caco-2 Cells; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D054418:Chemokine CCL20 / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011379:Prognosis; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C108355:CCL20 protein, human; C513384:CDH1 protein, human; C508606:CXCL8 protein, human; D015820:Cadherins; D054418:Chemokine CCL20; D016209:Interleukin-8; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: CCL20; CXCL8/interleukin-8; Colorectal cancer; Epithelial–mesenchymal transition; Prognosis