Graphical Abstract
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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.
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.
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).
Our data indicated that CCL16 downregulated the expression of CK19 and inhibited the malignant phenotype of HCC.
Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018;391(10127):1301–14. https://doi.org/10.1016/S0140-6736(18)30010-2.
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.
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.
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.
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.
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.
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.
Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008;134(6):1655–69. https://doi.org/10.1053/j.gastro.2008.03.003.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Lichterman JN, Reddy SM. Mast cells: a new frontier for cancer immunotherapy. Cells 2021;10(6):1270. https://doi.org/10.3390/cells10061270.
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.
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