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

iLIVER Pub Date : 2024-06-01 DOI:10.1016/j.iliver.2024.100096

Huigang Li , Jianyong Zhuo , Peiru Zhang , Jinyan Chen , Zuyuan Lin , Xudong Yang , Ruijie Zhao , Chenghao Cao , Wei Shen , Chiyu He , Hao Chen , Ting Lv , Xuyong Wei , Shusen Zheng , Xiao Xu , Di Lu

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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.

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CCL16 通过影响 CK19 表型抑制 HCC 的肿瘤增殖和转移

背景和目的Cytokeratin 19阳性（CK19+）肝细胞癌（HCC）是一种侵袭性亚型，预后较差。肝硬化背景下 CK19+ HCC 的发生和发展仍不清楚。本研究调查了肝硬化相关基因C-C mot chemokine ligand 16（CCL16）在CK19+ HCC发展过程中的作用。方法分析了基因表达总库（GEO）、癌症基因组图谱（TCGA）和国际癌症基因组联盟（ICGC）的数据集，以筛选和验证与CK19+ HCC相关的基因。共有 102 例 HCC 患者被纳入组织芯片分析。为研究CCL16的生物学功能，进行了功能增益实验。结果GEO数据集分析表明，CK19+ HCC的CCL16表达量较低。在 TCGA 数据集和我们的 HCC 队列中，CCL16 的表达与 CK19 的表达呈负相关（P < 0.05），且其在瘤旁组织中的表达高于肿瘤组织（P < 0.001）。此外，CCL16的低表达与晚期和总生存率低有关（P < 0.05）。CCL16过表达会降低CK19的表达，影响HCC细胞的球形成能力。过表达 CCL16 可抑制 HCC 细胞系的细胞增殖、迁移和侵袭。免疫分析表明，CCL16 高表达的 HCC 有更多的肥大细胞浸润。结论我们的数据表明，CCL16 下调了 CK19 的表达，抑制了 HCC 的恶性表型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

iLIVER

CiteScore

0.60

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0.00%

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