Li Huigang, Zhuo Jianyong, Zhang Peiru, Chen Jinyan, Lin Zuyuan, Yang Xudong, Zhao Ruijie, Cao Chenghao, Shen Wei, He Chiyu, Chen Hao, Lv Ting, Wei Xuyong, Zheng Shusen, Xu Xiao, Lu Di
Zhejiang University School of Medicine, Hangzhou 310058, China.
Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First People's Hospital, Hangzhou 310006, China.
ILIVER. 2024 May 20;3(2):100096. doi: 10.1016/j.iliver.2024.100096. eCollection 2024 Jun.
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 ( < 0.05) and its expression was higher in para-tumor than tumor tissues ( < 0.001). Moreover, low CCL16 expression was related to advanced stage and poor overall survival ( < 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 ( < 0.001).
Our data indicated that CCL16 downregulated the expression of CK19 and inhibited the malignant phenotype of HCC.
细胞角蛋白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的发生发展尚不清楚。本研究探讨了肝硬化相关基因C-C基序趋化因子配体16（CCL16）在CK19+HCC发生发展中的作用。
分析来自基因表达综合数据库（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。共纳入102例HCC患者进行组织芯片分析。进行功能获得实验以研究CCL16的生物学功能。使用CIBERSORT研究CCL16与免疫浸润的相关性。
GEO数据集分析显示CK19+HCC中CCL16表达较低。在TCGA数据集和我们的HCC队列中，CCL16表达均与CK19表达呈负相关（<0.05），且其在癌旁组织中的表达高于肿瘤组织（<0.001）。此外，低CCL16表达与晚期和较差的总生存期相关（<0.05）。CCL16过表达下调CK19表达并影响HCC细胞的成球能力。CCL16过表达抑制HCC细胞系的细胞增殖、迁移和侵袭。免疫分析显示CCL16高表达的HCC有更多肥大细胞浸润。CCL16表达低且肥大细胞少的HCC患者预后最差（<0.001）。
我们的数据表明CCL16下调CK19表达并抑制HCC的恶性表型。
