Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou 310003, China.
NHC Key Laboratory of Combined Multi-organ Transplantation, Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou 310003, China.
Hepatobiliary Pancreat Dis Int. 2020 Oct;19(5):440-448. doi: 10.1016/j.hbpd.2019.12.006. Epub 2020 Jan 3.
Liver cirrhosis results from many forms of chronic damage, characterized by accumulation of extracellular matrix. The present study aimed to explore a potential non-invasive biomarker and its mechanism in the progression of liver cirrhosis.
Gene Expression Omnibus (GEO) dataset (GSE15654, n = 216) was analyzed to screen genes associated with progression of liver cirrhosis. A total of 181 plasma samples, including healthy control (HC, n = 20), chronic hepatitis B (CHB, n = 77) and HBV-related liver cirrhosis (LC, n = 84), were enrolled for validation. In vitro and in vivo experiments were employed for the mechanistic investigation.
GEO dataset analysis showed that relatively low mRNA-expression of CC motif chemokine ligand 16 (CCL16) was associated with elevated Child-Pugh score (P = 0.034) and worse prognosis (P = 0.025). Plasma CCL16 level decreased in a stepwise pattern, with a median concentration of 10.29, 6.57 and 4.47 ng/mL in the HC, CHB and LC groups, respectively (P<0.001). Low plasma CCL16 was significantly related to hepatic dysfunction both in the CHB and LC groups (P<0.05). Combination of CCL16 and ALT showed improved distinguishing capability for LC compared to either alone. In vitro, CCL16 expression was downregulated by lipopolysaccharide and hypoxia. Overexpression of CCL16 from human normal liver cell line (LO2) reduced the extracellular matrix associated proteins (Col1 and Col4) in human hepatic stellate cell line (LX-2). In vivo, the pathological feature of cirrhosis was alleviated by the hepatocyte-specific expression of CCL16.
CCL16 could be a feasible plasma marker to predict the occurrence and progression of liver cirrhosis. CCL16 might impact liver cirrhosis through inactivating hepatic stellate cells.
肝硬化是由多种形式的慢性损伤引起的，其特征是细胞外基质的积累。本研究旨在探索肝硬化进展中的一种潜在的非侵入性生物标志物及其机制。
分析基因表达综合数据库（GEO）数据集（GSE15654，n=216），以筛选与肝硬化进展相关的基因。共纳入181 例血浆样本，包括健康对照组（HC，n=20）、慢性乙型肝炎（CHB，n=77）和乙型肝炎相关肝硬化（LC，n=84），进行验证。通过体外和体内实验进行机制研究。
GEO 数据集分析表明，相对较低的 C 型趋化因子配体 16（CCL16）mRNA 表达与升高的 Child-Pugh 评分（P=0.034）和更差的预后（P=0.025）相关。血浆 CCL16 水平呈阶梯式下降，HC、CHB 和 LC 组的中位数浓度分别为 10.29、6.57 和 4.47ng/mL（P<0.001）。在 CHB 和 LC 组中，低血浆 CCL16 与肝功能障碍显著相关（P<0.05）。CCL16 与 ALT 的联合检测对 LC 的鉴别能力优于单独检测。体外，CCL16 表达受脂多糖和低氧的下调。人正常肝细胞系（LO2）过表达 CCL16 可减少人肝星状细胞系（LX-2）的细胞外基质相关蛋白（Col1 和 Col4）。体内，CCL16 的肝细胞特异性表达可减轻肝硬化的病理特征。
CCL16 可能是预测肝硬化发生和进展的一种可行的血浆标志物。CCL16 可能通过使肝星状细胞失活而影响肝硬化。
