Li Yan, Jiang Li-Na, Zhao Bo-Kang, Li Mei-Ling, Jiang Yi-Yun, Liu Yi-Si, Liu Shu-Hong, Zhu Li, Ye Xin, Zhao Jing-Min
Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China.
Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China.
World J Gastrointest Oncol. 2024 Aug 15;16(8):3651-3671. doi: 10.4251/wjgo.v16.i8.3651.
Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide, and metastasis is the main cause of early recurrence and poor prognosis. However, the mechanism of metastasis remains poorly understood.
To determine the possible mechanism affecting HCC metastasis and provide a possible theoretical basis for HCC treatment.
The candidate molecule lecithin-cholesterol acyltransferase (LCAT) was screened by gene microarray and bioinformatics analysis. The expression levels of LCAT in clinical cohort samples was detected by quantitative real-time polymerase chain reaction and western blotting. The proliferation, migration, invasion and tumor-forming ability were measured by Cell Counting Kit-8, Transwell cell migration, invasion, and clonal formation assays, respectively. Tumor formation was detected in nude mice after gene knockdown or overexpression. The immunohistochemistry for Ki67, E-cadherin, N-cadherin, matrix metalloproteinase 9 and vascular endothelial growth factor were performed in liver tissues to assess the effect of LCAT on HCC. Gene set enrichment analysis (GSEA) on various gene signatures were analyzed with GSEA version 3.0. Three machine-learning algorithms (random forest, support vector machine, and logistic regression) were applied to predict HCC metastasis in The Cancer Genome Atlas and GEO databases.
was identified as a novel gene relating to HCC metastasis by using gene microarray in HCC tissues. LCAT was significantly downregulated in HCC tissues, which is correlated with recurrence, metastasis and poor outcome of HCC patients. Functional analysis indicated that LCAT inhibited HCC cell proliferation, migration and invasion both and . Clinicopathological data showed that LCAT was negatively associated with HCC size and metastasis (HCC size ≤ 3 cm 3-9 cm, < 0.001; 3-9 cm > 9 cm, < 0.01; metastatic-free HCC extrahepatic metastatic HCC, < 0.05). LCAT suppressed the growth, migration and invasion of HCC cell lines PI3K/AKT/mTOR signaling. Our results indicated that the logistic regression model based on LCAT, TNM stage and the serum level of α-fetoprotein in HCC patients could effectively predict high metastatic risk HCC patients.
is downregulated at translational and protein levels in HCC and might inhibit tumor metastasis attenuating PI3K/AKT/mTOR signaling. LCAT is a prognostic marker and potential therapeutic target for HCC.
肝细胞癌（HCC）是全球癌症死亡的主要原因，转移是早期复发和预后不良的主要原因。然而，转移机制仍知之甚少。
确定影响HCC转移的可能机制，并为HCC治疗提供可能的理论依据。
通过基因芯片和生物信息学分析筛选候选分子卵磷脂胆固醇酰基转移酶（LCAT）。采用定量实时聚合酶链反应和蛋白质印迹法检测临床队列样本中LCAT的表达水平。分别通过细胞计数试剂盒-8、Transwell细胞迁移、侵袭和克隆形成试验检测细胞增殖、迁移、侵袭和肿瘤形成能力。基因敲低或过表达后，在裸鼠中检测肿瘤形成。对肝组织进行Ki67、E-钙黏蛋白、N-钙黏蛋白、基质金属蛋白酶9和血管内皮生长因子的免疫组织化学检测，以评估LCAT对HCC的影响。使用GSEA 3.0版本对各种基因特征进行基因集富集分析（GSEA）。应用三种机器学习算法（随机森林、支持向量机和逻辑回归）在癌症基因组图谱和GEO数据库中预测HCC转移。
通过对HCC组织进行基因芯片分析，确定LCAT是与HCC转移相关的新基因。LCAT在HCC组织中显著下调，这与HCC患者的复发、转移和不良预后相关。功能分析表明，LCAT在体内和体外均抑制HCC细胞增殖、迁移和侵袭。临床病理数据显示，LCAT与HCC大小和转移呈负相关（HCC大小≤3 cm对3 - 9 cm，P < 0.001；3 - 9 cm对> 9 cm，P < 0.01；无转移HCC对肝外转移HCC，P < 0.05）。LCAT通过PI3K/AKT/mTOR信号通路抑制HCC细胞系的生长、迁移和侵袭。我们的结果表明，基于LCAT、TNM分期和HCC患者血清甲胎蛋白水平的逻辑回归模型可以有效预测高转移风险的HCC患者。
LCAT在HCC的翻译和蛋白质水平上被下调，可能通过减弱PI3K/AKT/mTOR信号通路抑制肿瘤转移。LCAT是HCC的预后标志物和潜在治疗靶点。
