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Original Article | Open Access

CCL16 inhibits tumor proliferation and metastasis in HCC by impacting CK19 phenotype

Huigang Lia,1, Jianyong Zhuob,1, Peiru Zhangc,1, Jinyan Chena,1, Zuyuan Lina,d, Xudong Yange, Ruijie Zhaoa, Chenghao Caoa, Wei Shena, Chiyu Hea, Hao Chena, Ting Lvd, Xuyong Weif,g, Shusen Zhengg,h,i( ), Xiao Xuf,g,j( ), Di Luf,g( )
Zhejiang University School of Medicine, Hangzhou 310000, China
Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People’s Hospital, Hangzhou 310006, China
The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou 310000, China
Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310000, China
Hangzhou Normal University, Hangzhou 310000, China
Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People’s Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China
NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 310000, China
Institute of Translational Medicine, Zhejiang University, Hangzhou 310000, China

1 These authors contributed equally to this work.

Show Author Information

Graphical Abstract

CK19-positive (CK19+) HCC is an aggressive subtype demonstrating poor outcome. The initiation and development of CK19+ HCC in the background of liver cirrhosis remains unclear. Our previous study has reported CCL16 could reduce liver cirrhosis through inactivating of hepatic stellate cells. This study aims to investigate the role of cirrhosis related gene, C–C motif chemokine ligand 16 (CCL16), in the development of CK19+ HCC. In this study, we found a negative correlation between CCL16 immunostaining and BCLC stage. Besides, CCL16 could downregulate the expression of CK19 and inhibit the malignant phenotype of HCC. Moreover, high CCL16 expression HCC had more infiltration of mast cells. HCC patients with both low CCL16 expression and low mast cells had worst prognosis.

Abstract

Background and aims

Cytokeratin 19–positive (CK19+) hepatocellular carcinoma (HCC) is an aggressive subtype with poor outcomes. The initiation and development of CK19+ HCC in the background of liver cirrhosis remains unclear. This study investigated the role of the cirrhosis-related gene C–C motif chemokine ligand 16 (CCL16) in the development of CK19+ HCC.

Methods

Datasets from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) were analyzed to screen and validate the genes associated with CK19+ HCC. A total of 102 HCC patients were included for tissue microarray analysis. Gain-of-function experiments were conducted to investigate the biological functions of CCL16. CIBERSORT was used to investigate the correlation of CCL16 and immune infiltration.

Results

GEO dataset analysis showed that CK19+ HCC had lower expression of CCL16. In both TCGA dataset and our HCC cohort, CCL16 expression was negatively correlated with CK19 expression (P ​< ​0.05) and its expression was higher in para-tumor than tumor tissues (P ​< ​0.001). Moreover, low CCL16 expression was related to advanced stage and poor overall survival (P ​< ​0.05). CCL16 overexpression downregulated CK19 expression and impacted the sphere formation ability of HCC cells. Overexpression of CCL16 inhibited the cell proliferation, migration, and invasion of HCC cell lines. Immune analysis showed HCC with high CCL16 expression had more infiltration of mast cells. HCC patients with both low CCL16 expression and low mast cells had the worst prognosis (P ​< ​0.001).

Conclusion

Our data indicated that CCL16 downregulated the expression of CK19 and inhibited the malignant phenotype of HCC.

Keywords

Hepatocellular carcinomaPrognosisCytokeratin 19C–C motif chemokine ligand 16Mast cells

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iLIVER
Volume 3 Issue 2,
June 2024
Article number: 100096
DOI: 10.1016/j.iliver.2024.100096
Cite this article:
Li H, Zhuo J, Zhang P, et al. CCL16 inhibits tumor proliferation and metastasis in HCC by impacting CK19 phenotype. iLIVER, 2024, 3(2): 100096. https://doi.org/10.1016/j.iliver.2024.100096

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Received: 10 March 2024
Revised: 06 April 2024
Accepted: 09 May 2024
Published: 20 May 2024
© 2024 Tsinghua University Press.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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