AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home iLIVER Article
Article Link
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
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 carcinomaCytokeratin 19C–C motif chemokine ligand 16Mast cellsPrognosis

References

[1]

Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018;391(10127):1301–14. https://doi.org/10.1016/S0140-6736(18)30010-2.
Crossref Google Scholar
[2]

Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.
Crossref Google Scholar
[3]

Chen WQ, Zeng HM, Zheng RS, et al. Cancer incidence and mortality in China, 2007. Chin J Cancer Res 2012;24(1):1–8. https://doi.org/10.1007/s11670-012-0001-6.
Crossref Google Scholar
[4]

Li Q, Cao M, Lei L, et al. Burden of liver cancer: from epidemiology to prevention. Chin J Cancer Res. 2022;34(6):554–66. https://doi.org/10.21147/j.issn.1000-9604.2022.06.02.
Crossref Google Scholar
[5]

Chen J, Shen T, Li J, et al. Clinical practice guideline on liver transplantation for hepatocellular carcinoma in China (2021 edition). Chin Med J 2022;135(24):2911–3. https://doi.org/10.1097/CM9.0000000000002515.
Crossref Google Scholar
[6]

Wang K, Dong L, Lu Q, et al. Incorporation of protein induced by vitamin K absence or antagonist-Ⅱ into transplant criteria expands beneficiaries of liver transplantation for hepatocellular carcinoma: a multicenter retrospective cohort study in China. Int J Surg 2023;109(12):4135–44. https://doi.org/10.1097/JS9.0000000000000729.
Crossref Google Scholar
[7]

Chan SL, Wong VWS, Qin S, et al. Infection and cancer: the case of hepatitis B. J Clin Oncol 2016;34(1):83–90. https://doi.org/10.1200/JCO.2015.61.5724.
Crossref Google Scholar
[8]

Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008;134(6):1655–69. https://doi.org/10.1053/j.gastro.2008.03.003.
Crossref Google Scholar
[9]

Li S, Liu R, Pan Q, et al. De novo lipogenesis is elicited dramatically in human hepatocellular carcinoma especially in hepatitis C virus-induced hepatocellular carcinoma. MedComm 2020;1(2):178–87. https://doi.org/10.1002/mco2.15.
Crossref Google Scholar
[10]

Ehling J, Bartneck M, Wei X, et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 2014;63(12):1960–71. https://doi.org/10.1136/gutjnl-2013-306294.
Crossref Google Scholar
[11]

Korbecki J, Kojder K, Simińska D, et al. CC chemokines in a tumor: a review of pro-cancer and anti-cancer properties of the ligands of receptors CCR1, CCR2, CCR3, and CCR4. Int J Mol Sci 2020;21(21):8412. https://doi.org/10.3390/ijms21218412.
Crossref Google Scholar
[12]

Lu D, Lin Z, Wang R, et al. Multi-omics profiling reveals Chitinase-3-like protein 1 as a key mediator in the crosstalk between sarcopenia and liver cancer. Redox Biol 2022;58:102538. https://doi.org/10.1016/j.redox.2022.102538.
Crossref Google Scholar
[13]

Vogel A, Cervantes A, Chau I, et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(Suppl 4):iv238-iv255. https://doi.org/10.1093/annonc/mdy308.
Crossref Google Scholar
[14]
European Association for the Study of the Liver Electronic address: easloffice@easloffice eu, European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2018;69(1): 182–236. https://doi.org/10.1016/j.jhep.2018.03.019.
Crossref
[15]

Liang HR, Hsieh CE, Lin KH, et al. Living donor liver transplantation for hepatocellular carcinoma beyond the Milan criteria: outcome of expanded criteria in tumor size. BMC Surg 2021;21(1):401. https://doi.org/10.1186/s12893-021-01403-z.
Crossref Google Scholar
[16]

Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol 2017;14(4):203–17. https://doi.org/10.1038/nrgastro.2016.193.
Crossref Google Scholar
[17]

Miltiadous O, Sia D, Hoshida Y, et al. Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation. J Hepatol 2015;63(6):1368–77. https://doi.org/10.1016/j.jhep.2015.07.025.
Crossref Google Scholar
[18]

Zhuo JY, Lu D, Tan WY, et al. CK19-positive hepatocellular carcinoma is a characteristic subtype. J Cancer 2020;11(17):5069–77. https://doi.org/10.7150/jca.44697.
Crossref Google Scholar
[19]

Zhuo J, Lu D, Lin Z, et al. The distinct responsiveness of cytokeratin 19-positive hepatocellular carcinoma to regorafenib. Cell Death Dis 2021;12(12):1084. https://doi.org/10.1038/s41419-021-04320-4.
Crossref Google Scholar
[20]

Strasly M, Doronzo G, Cappello P, et al. CCL16 activates an angiogenic program in vascular endothelial cells. Blood 2004;103(1):40–9. https://doi.org/10.1182/blood-2003-05-1387.
Crossref Google Scholar
[21]

Kim IS, Jang SW, Sung HJ, et al. Differential CCR1-mediated chemotaxis signaling induced by human CC chemokine HCC-4/CCL16 in HOS cells. FEBS Lett 2005;579(27):6044–8. https://doi.org/10.1016/j.febslet.2005.09.064.
Crossref Google Scholar
[22]

Shen W, Zhang X, Tang J, et al. CCL16 maintains stem cell-like properties in breast cancer by activating CCR2/GSK3β/β-catenin/OCT4 axis. Theranostics 2021;11(5):2297–317. https://doi.org/10.7150/thno.51000.
Crossref Google Scholar
[23]

Cappello P, Caorsi C, Bosticardo M, et al. CCL16/LEC powerfully triggers effector and antigen-presenting functions of macrophages and enhances T cell cytotoxicity. J Leukoc Biol 2004;75(1):135–42. https://doi.org/10.1189/jlb.0403146.
Crossref Google Scholar
[24]

Cappello P, Fraone T, Barberis L, et al. CC-chemokine ligand 16 induces a novel maturation program in human immature monocyte-derived dendritic cells. J Immunol 2006;177(9):6143–51. https://doi.org/10.4049/jimmunol.177.9.6143.
Crossref Google Scholar
[25]

Zhuo JY, Lu D, Lin ZY, et al. CC motif chemokine ligand 16 inhibits the progression of liver cirrhosis via inactivating hepatic stellate cells. Hepatobiliary Pancreat Dis Int 2020;19(5):440–8. https://doi.org/10.1016/j.hbpd.2019.12.006.
Crossref Google Scholar
[26]

Kang MJ, Lee S, Jung U, et al. Inhibition of hepatic stellate cell activation suppresses tumorigenicity of hepatocellular carcinoma in mice. Am J Pathol 2021;191(12):2219–30. https://doi.org/10.1016/j.ajpath.2021.08.004.
Crossref Google Scholar
[27]

Liu B, Zhou Z, Jin Y, et al. Hepatic stellate cell activation and senescence induced by intrahepatic microbiota disturbances drive progression of liver cirrhosis toward hepatocellular carcinoma. J Immunother Cancer 2022;10(1):e003069. https://doi.org/10.1136/jitc-2021-003069.
Crossref Google Scholar
[28]

Li H, Lin Z, Zhuo J, et al. TNFR2 is a potent prognostic biomarker for post-transplant lung metastasis in patients with hepatocellular carcinoma. Chin J Cancer Res. 2023;35(1):66–80. https://doi.org/10.21147/j.issn.1000-9604.2023.01.07.
Crossref Google Scholar
[29]

Gao D, Vahdat LT, Wong S, et al. Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer Res 2012;72(19):4883–9. https://doi.org/10.1158/0008-5472.CAN-12-1223.
Crossref Google Scholar
[30]

Dominguez C, David JM, Palena C. Epithelial-mesenchymal transition and inflammation at the site of the primary tumor. Semin Cancer Biol 2017;47:177–84. https://doi.org/10.1016/j.semcancer.2017.08.002.
Crossref Google Scholar
[31]

Sousa Da Silva RX, Muellhaupt B, Dutkowski P, et al. Liver transplantation for malignant liver tumors. iLIVER 2022;1(1):3–11. https://doi.org/10.1016/j.iliver.2022.04.002.
Crossref Google Scholar
[32]

Yang CL, Song R, Hu JW, et al. Integrating single-cell and bulk RNA sequencing reveals CK19 + cancer stem cells and their specific SPP1 + tumor-associated macrophage niche in HBV-related hepatocellular carcinoma. Hepatol Int 2024;18(1):73–90. https://doi.org/10.1007/s12072-023-10615-9.
Crossref Google Scholar
[33]

Nieto MA, Huang RYJ, Jackson RA, et al. Emt: 2016. Cell 2016;166(1):21–45. https://doi.org/10.1016/j.cell.2016.06.028.
Crossref Google Scholar
[34]

Huang Y, Hong W, Wei X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol 2022;15(1):129. https://doi.org/10.1186/s13045-022-01347-8.
Crossref Google Scholar
[35]

Brabletz S, Schuhwerk H, Brabletz T, et al. Dynamic EMT: a multi-tool for tumor progression. EMBO J 2021;40(18):e108647. https://doi.org/10.15252/embj.2021108647.
Crossref Google Scholar
[36]

Shibue T, Weinberg RA. EMT, CSCs, and drug resistan the mechanistic link and clinical implications. Nat Rev Clin Oncol 2017;14(10):611–29. https://doi.org/10.1038/nrclinonc.2017.44.
Crossref Google Scholar
[37]

Lou J, Geng S, He W, et al. Zyxin inhibits the epithelial-mesenchymal transition process in gastric cancer by upregulating SIRT1. MedComm 2023;4(5):e357. https://doi.org/10.1002/mco2.357.
Crossref Google Scholar
[38]

Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013;19(11):1423–37. https://doi.org/10.1038/nm.3394.
Crossref Google Scholar
[39]

Pitt JM, Marabelle A, Eggermont A, et al. Targeting the tumor microenvironment: removing obstruction to anticancer immune responses and immunotherapy. Ann Oncol 2016;27(8):1482–92. https://doi.org/10.1093/annonc/mdw168.
Crossref Google Scholar
[40]

Shi S, Ye L, Yu X, et al. Focus on mast cells in the tumor microenvironment: current knowledge and future directions. Biochim Biophys Acta Rev Cancer 2023;1878(1):188845. https://doi.org/10.1016/j.bbcan.2022.188845.
Crossref Google Scholar
[41]

Siebenhaar F, Redegeld FA, Bischoff SC, et al. Mast cells as drivers of disease and therapeutic targets. Trends Immunol 2018;39(2):151–62. https://doi.org/10.1016/j.it.2017.10.005.
Crossref Google Scholar
[42]

Shi Y, Wang Y, Dong H, et al. Crosstalk of ferroptosis regulators and tumor immunity in pancreatic adenocarcinoma: novel perspective to mRNA vaccines and personalized immunotherapy. Apoptosis 2023;28(9-10):1423–35. https://doi.org/10.1007/s10495-023-01868-8.
Crossref Google Scholar
[43]

Wang S, Wang R, Xu N, et al. SULT2B1-CS-DOCK2 axis regulates effector T-cell exhaustion in HCC microenvironment. Hepatology 2023;78(4):1064–78. https://doi.org/10.1097/HEP.0000000000000025.
Crossref Google Scholar
[44]

Lichterman JN, Reddy SM. Mast cells: a new frontier for cancer immunotherapy. Cells 2021;10(6):1270. https://doi.org/10.3390/cells10061270.
Crossref Google Scholar
[45]

Sulsenti R, Jachetti E. Frenemies in the microenvironment: harnessing mast cells for cancer immunotherapy. Pharmaceutics 2023;15(6):1692. https://doi.org/10.3390/pharmaceutics15061692.
Crossref Google Scholar
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

231

Views

0

Crossref

0

Scopus

Altmetrics
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/).
Return