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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Lecithin-cholesterol acyltransferase is a potential tumor suppressor and predictive marker for hepatocellular carcinoma metastasis
Yan Li, Li-Na Jiang, Bo-Kang Zhao, Mei-Ling Li, Yi-Yun Jiang, Yi-Si Liu, Shu-Hong Liu, Li Zhu, Xin Ye, Jing-Min Zhao
Yan Li, Li-Na Jiang, Mei-Ling Li, Yi-Yun Jiang, Shu-Hong Liu, Li Zhu, Department of Pathology and Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
Bo-Kang Zhao, Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
Yi-Si Liu, First Department of Liver Disease Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
Xin Ye, Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Xin Ye, Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100190, China
Jing-Min Zhao, Department of Pathology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
Co-first authors: Yan Li and Li-Na Jiang.
Co-corresponding authors: Xin Ye and Jing-Min Zhao.
Author contributions: Li Y contributed to performing the experiments, analyzing the data, study concept and design; Jiang LN contributed to writing and revising the manuscript, study concept and design; Zhao BK contributed to collecting clinical specimens, revision and language polishing of manuscript; Li ML contributed to performing immunohistochemical experiments; Jiang YY contributed to constructing plasmids; Liu YS contributed to collecting clinical specimens; Liu SH contributed to performing pathological diagnosis; Zhu L contributed to capturing immunohistochemical images; Ye X contributed to supervising the project and performing critical revision of the manuscript; Zhao JM contributed to study concept and design, analyzing the data, financial support, supervising the project, and performing critical revision of the manuscript; and all authors discussed the results, commented on the manuscript, and read and approved the final manuscript. Li Y and Jiang LN contributed equally to this work as co-first authors; Ye X and Zhao JM contributed equally (critical revision) to this work as co-corresponding authors.
Supported by the National Natural Science Foundation of China, No. 92159305; and National Key R&D Program of China, No. 2023YFC2308104.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Chinese PLA General Hospital.
Conflict-of-interest statement: The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Data sharing statement: The authors confirm that the data supporting the findings of this study are available within the article and its
Supplementary materials.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Jing-Min Zhao, MD, Professor, Department of Pathology, The Fifth Medical Center of Chinese PLA General Hospital, No. 100 Xisihuan Middle Road, Beijing 100039, China.
jmzhao302@163.com
Received: April 24, 2024
Revised: May 27, 2024
Accepted: June 18, 2024
Published online: August 15, 2024
Processing time: 105 Days and 20.8 Hours
BACKGROUND
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.
AIM
To determine the possible mechanism affecting HCC metastasis and provide a possible theoretical basis for HCC treatment.
METHODS
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 LCAT 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.
RESULTS
LCAT 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 in vitro and in vivo. Clinicopathological data showed that LCAT was negatively associated with HCC size and metastasis (HCC size ≤ 3 cm vs 3-9 cm, P < 0.001; 3-9 cm vs > 9 cm, P < 0.01; metastatic-free HCC vs extrahepatic metastatic HCC, P < 0.05). LCAT suppressed the growth, migration and invasion of HCC cell lines via 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.
CONCLUSION
LCAT is downregulated at translational and protein levels in HCC and might inhibit tumor metastasis via attenuating PI3K/AKT/mTOR signaling. LCAT is a prognostic marker and potential therapeutic target for HCC.
Core Tip: For the first time, we found that lecithin-cholesterol acyltransferase, a molecule related to lipid metabolism, is closely related to the metastasis of hepatocellular carcinoma (HCC), which provides a new prospective for studying the recurrence and metastasis mechanism of HCC, and also finds strong evidence for revealing the connection between lipid metabolism and HCC metastasis.
