title: CXCR2/CXCL5 axis contributes to epithelial-mesenchymal transition of HCC cells through activating PI3K/Akt/GSK-3β/Snail signaling.
abstract: Upregulation of CXCR2 in tumor cells has been documented in several types of cancer. As one of its ligands, CXCL5 is associated with neutrophil infiltration and poor prognosis in hepatocellular carcinoma (HCC). However, little is known about the role of the CXCR2/CXCL5 axis in the invasion and metastasis of HCC cells. In this study, we examined CXCR2 expression in human HCC cell lines and in three independent cohorts of HCC patients. The molecular effects of high expression levels of CXCR2 and CXCL5 in HCC cells were determined using qRT-PCR, western blot analysis, immunofluorescence, matrigel invasion assay, and xenograft mouse models. We found that high levels of CXCR2 correlated with progression and poor prognosis in human HCC. CXCR2/CXCL5 together promoted cell spreading by inducing the epithelial-mesenchymal transition (EMT) through activation of the PI3K/Akt/GSK-3β/Snail signaling pathway. In clinical HCC samples, high expression of both CXCR2 and CXCL5 showed a significant correlation with the activation of PI3K/Akt/GSK-3β/Snail signaling and EMT phenotype. In conclusion, our data showed that the CXCR2/CXCL5 axis contributes to EMT of HCC cells through activating PI3K/Akt/GSK-3β/Snail signaling, and it may serve as a potential therapeutic target.
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Shao-Lai
authors.initials: SL
authors.lastname: Zhou
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Zheng-Jun
authors.initials: ZJ
authors.lastname: Zhou
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai 200032, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Hu
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai 200032, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai 200032, China.
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Huang
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai 200032, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: dai.zhi@zs-hospital.sh.cn.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Dai
authors.affiliation: Liver Surgery Department, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Fudan University, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai, China. Electronic address: zhou.jian@zs-hospital.sh.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D054365:Chemokine CXCL5 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D054365:Chemokine CXCL5; D023063:Receptors, Interleukin-8B; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: CXCL5; CXCR2; Epithelial–mesenchymal transition; Hepatocellular carcinoma; Metastasis