Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2015; 21(2): 475-483
Published online Jan 14, 2015. doi: 10.3748/wjg.v21.i2.475
Chemokine ligand 20 enhances progression of hepatocellular carcinoma via epithelial-mesenchymal transition
Ke-Zhu Hou, Zhi-Qiang Fu, Hua Gong
Ke-Zhu Hou, Zhi-Qiang Fu, Hua Gong, Department of First General Surgery, Shidong Hospital, Shanghai 200438, China
Author contributions: Fu ZQ and Gong H designed the study; Hou KZ performed the majority of experiments; Fu ZQ analyzed the data; Gong H wrote the manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Hua Gong, MD, PhD, Department of First General Surgery, Shidong Hospital, No. 999 Shiguang Road, Yangpu district, Shanghai 200438, China.
Telephone: +86-21-65881977 Fax: +86-21-65881977
Received: April 20, 2014
Peer-review started: April 21, 2014
First decision: May 13, 2014
Revised: June 8, 2014
Accepted: July 11, 2014
Article in press: July 11, 2014
Published online: January 14, 2015

AIM: To identify the mechanisms of chemokine ligand 20 (CCL20)-induced hepatocellular carcinoma (HCC) metastasis and evaluate it as a prognostic marker.

METHODS: Expression of CCL20 was evaluated by immunohistochemistry in HCC tissues from 62 patients who underwent curative resection. The relationship between CCL20 expression and clinicopathologic features was analyzed. Univariate and multivariate analyses were performed to evaluate its predictive value for recurrence and survival of HCC patients. The expression levels of epithelial-mesenchymal transition (EMT)-and signaling pathway-related proteins were evaluated by Western blotting and immunocytochemistry. The effects of CCL20 on HCC cell proliferation and migration were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenoltetrazolium bromide (MTT) and Transwell assays.

RESULTS: CCL20 immunoreactivity was detected in all 62 patient specimens. CCL20 expression was associated with preoperative alpha-fetoprotein level (P = 0.043), tumor size (P = 0.000), tumor number (P = 0.008), vascular invasion (P = 0.014), and tumor differentiation (P = 0.007). Patients with high CCL20 expression had poorer recurrence-free and overall survivals compared to those with low CCL20 expression (both P < 0.001). CCL20 induced EMT-like changes in HCC cells and increased their proliferation and migration ability (P < 0.05). Western blotting and immunofluorescence staining showed that CCL20 induced an EMT-like phenotype in HCC cells, and increased expression of phosphorylated AKT, β-catenin and vimentin, and decreased E-cadherin expression (P < 0.05). The correlation analysis revealed that high CCL20 expression in HCC tissue specimens was negatively correlated with E-cadherin expression (13.33%, 4/30), and positively correlated with vimentin (90.0%, 27/30), β-catenin (96.67%, 29/30) and p-AKT (76.67%, 23/30) expression.

CONCLUSION: CCL20 expression is associated with HCC recurrence and patient survival and promotes HCC cell proliferation and migration by inducing EMT-like changes via PI3K/AKT and Wnt/β-catenin pathways.

Keywords: Chemokine ligand 20, Phosphoinositide kinase-3/AKT, Prognosis, Wnt/β-catenin, Epithelial-mesenchymal transition, Hepatocellular carcinoma

Core tip: This study examined the expression and prognostic value of chemokine ligand 20 in hepatocellular carcinoma. The results indicate that increased expression of this protein regulates the growth and migration of hepatocellular carcinoma cells and epithelial-mesenchymal transition via phosphoinositide kinase-3/AKT, and Wnt/β-catenin signaling pathways and is therefore a potential treatment target.