Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Dec 27, 2024; 16(12): 1480-1492
Published online Dec 27, 2024. doi: 10.4254/wjh.v16.i12.1480
Hypoxia upregulates hepatic angiopoietin-2 transcription to promote the progression of hepatocellular carcinoma
Jun-Ling Yang, Jie Yang, Rong-Fei Fang, Wen-Li Sai, Deng-Fu Yao, Min Yao
Jun-Ling Yang, Wen-Li Sai, Deng-Fu Yao, Min Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University and Department of Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China
Jie Yang, Department of Biology, Life Science School of Nantong University, Nantong 226009, Jiangsu Province, China
Rong-Fei Fang, Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
Co-first authors: Jun-Ling Yang and Jie Yang.
Co-corresponding authors: Deng-Fu Yao and Min Yao.
Author contributions: Yang JL and Yang J contributed equally to this study, they are co-first authors of this manuscript. Yang JL and Yang J conceived the study and analyzed and interpreted the data; Yang J, Fang RF, and Yao M performed the experiments; Sai WL and Yao DF performed the statistical and bioinformatics analyses; Yang J, Fang RF, and Yao M acquired the materials and data; Yao DF and Yao M acquired the funding and wrote the manuscript, they contributed equally to this study and are the co-corresponding authors of this manuscript. All the authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 32470985 and No. 81673241.
Institutional review board statement: Patient recruitment was approved by the Ethics Committee of the Affiliated Hospital of Nantong University (No. 2018-L015).
Institutional animal care and use committee statement: The study involving the rat model was approved by the guidelines of the Animal Care and Use Committee of Nantong University (No. 20190304-001).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Deng-Fu Yao, MD, PhD, Professor, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, No. 20 West Temple Road, Nantong 226001, Jiangsu Province, China. yaodf@ahnmc.com
Received: June 27, 2024
Revised: August 22, 2024
Accepted: September 13, 2024
Published online: December 27, 2024
Processing time: 154 Days and 15 Hours
Abstract
BACKGROUND

Angiopoietin-2 (Ang-2) level is related to hepatocellular carcinoma (HCC) progression. However, the dynamic expression and regulatory mechanism of Ang-2 remain unclear.

AIM

To investigate Ang-2 levels in chronic liver diseases and validate early monitoring value with a dynamic model in hepatocarcinogenesis.

METHODS

Sprague-Dawley rats in hepatocarcinogenesis were induced with diet 2-fluorenylacet-amide, and grouped based on liver histopathology by hematoxylin and eosin staining. Differently expressed genes or Ang-2 mRNA in livers were analyzed by whole-genome microarray. Ang-2 levels in chronic liver diseases were detected by an enzyme-linked immunosorbent assay.

RESULTS

Clinical observation reveled that the circulating levels of Ang-2 and hypoxia-inducible factor-1α (HIF-1α) in patients with chronic liver diseases were progressively increased from benign to HCC (P < 0.001). Dynamic model validated that the up-regulated Ang-2 in liver and blood was positively correlated with HIF-1α in hepatocarcinogenesis (P < 0.001). Mechanistically, Ang-2 was regulated by HIF-1α. When specific HIF-1α- microRNAs transfected into HCC cells, the cell proliferation significantly inhibited, HIF-1α and Ang-2 down-regulated, and also affected epithelial-mesenchymal transition via increasing E-cadherin to block cell invasion or migration with reducing of snail, twist and vimentin.

CONCLUSION

Hypoxia-induced Ang-2 up-regulating expression might serve as a sensitive early monitoring biomarker for hepatocarcinogenesis or HCC metastasis.

Keywords: Angiopoietin-2; Hypoxia-inducible factor-1α; Hepatocarcinogenesis; Dynamic model; Metastasis

Core Tip: In this study, the expression of angiopoietin-2 (Ang-2) in the malignant progression of chronic benign liver diseases was investigated, and its value in monitoring hepatocellular carcinoma (HCC) progression in a dynamic rat model was validated. In a hypoxic environment, Ang-2 activation is associated with the malignant transformation of hepatocytes or the metastasis of HCC cells. Mechanistically, the down-regulation of hypoxia-inducible factor-1α transcription inhibited Ang-2 expression and the epithelial-mesenchymal transition in HCC. These results suggest that there are positive correlations between hypoxia-inducible factor-1α and Ang-2 in benign liver diseases and hepatocyte malignant progression, suggesting that abnormal Ang-2 expression might be a sensitive early biomarker for monitoring the occurrence or metastasis of HCC.