Copyright
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Granulocyte-macrophage colony-stimulating factor protects mice against hepatocellular carcinoma by ameliorating intestinal dysbiosis and attenuating inflammation
Yong-Na Wu, Lei Zhang, Tuo Chen, Xun Li, Li-Hong He, Guang-Xiu Liu
Yong-Na Wu, Tuo Chen, Guang-Xiu Liu, Key Laboratory of Desert and Desertification, Northwest Institute of Eco-Environment and Resources, Chinese Academy of Sciences, Lanzhou 730000, Gansu Province, China
Yong-Na Wu, Tuo Chen, Guang-Xiu Liu, Key Laboratory of Extreme Environmental Microbial Resources and Engineering of Gansu Province, Lanzhou 730000, Gansu Province, China
Yong-Na Wu, Tuo Chen, Guang-Xiu Liu, University of Chinese Academy of Sciences, Beijing 100049, China
Yong-Na Wu, Lei Zhang, Xun Li, Li-Hong He, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou 730000, Gansu Province, China
Yong-Na Wu, Lei Zhang, Xun Li, Key Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, Lanzhou 730000, Gansu Province, China
Author contributions: Wu YN, Chen T, Li X and Liu GX conceived and designed the study; Wu YN and Zhang L performed the experiments; Wu YN and He LH wrote the manuscript; all authors read and approved the final manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Supported by: The National Natural Science Foundation of China, No. 31960236 and 31770536; and the Lanzhou Talent Innovation and Entrepreneurship Project, No. 2019-RC-34.
Institutional review board statement: This study was approved by the Ethics Committee of the First Hospital of Lanzhou University, No. LLYYLL-2017-18.
Institutional animal care and use committee statement: All procedures involving animals were approved by the Ethics Committee of the First Hospital of Lanzhou University, No. LLYYLL-2017-18.
Conflict-of-interest statement: There are no conflicts of interest in this study.
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: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Guang-Xiu Liu, PhD, Chairman, Research Scientist, Northwest Institute of Eco-Environment and Resources, University of Chinese Academy of Sciences, No. 320 Donggang West Road, Chengguan District, Lanzhou 730000, Gansu Province, China. liugx@lzb.ac.cn
Received: April 1, 2020
Peer-review started: April 1, 2020
First decision: June 4, 2020
Revised: June 11, 2020
Accepted: August 25, 2020
Article in press: August 25, 2020
Published online: September 28, 2020
BACKGROUND
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. The gut microbiota can help maintain healthy metabolism and immunity. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical factor in promoting health and homeostasis; it promotes intestinal immunity, stimulates bone marrow precursors to generate macrophage colonies, and enhances the antibacterial and antitumor activity of circulating monocytes. As such, GM-CSF may protect against HCC development by regulating immunity as well as intestinal microecology.
AIM
To investigate the impact of GM-CSF on the gut microbiome and metabolic characteristics of HCC.
METHODS
Thirty-six male BALB/c nude mice were divided into three groups: Control (n = 10), HCC (n = 13), and HCC + GM-CSF (GM-CSF overexpression, n = 13). We utilized HCC cells to establish orthotopic transplantation tumor models of HCC with normal and over-expressing GM-CSF. Liver injury, immune inflammatory function and intestinal barrier function were evaluated. The fecal microbiome and metabolome were studied using 16S rRNA absolute quantification sequencing and gas chromatography-mass spectrometry.
RESULTS
GM-CSF overexpression significantly affected the gut microbiome of mice with HCC and resulted in a high abundance of organisms of the genera Roseburia, Blautia and Butyricimonass, along with a significant reduction in Prevotella, Parabacteroides, Anaerotruncus, Streptococcus, Clostridium, and Mucispirillum. Likewise, GM-CSF overexpression resulted in a substantial increase in fecal biotin and oleic acid levels, along with a prominent decrease in the fecal succinic acid, adenosine, fumaric acid, lipoic acid, and maleic acid levels. Correlation analysis revealed that the intestinal microbiota and fecal metabolites induced by GM-CSF were primarily involved in pathways related to reducing the inflammatory response, biotin metabolism, and intestinal barrier dysfunction.
CONCLUSION
GM-CSF can protect against HCC development by regulating immunity and modulating the abundance of specific intestinal microorganisms and their metabolites. This study provides new insights into the therapeutic approaches for HCC.
Core Tip: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical factor in promoting intestinal immunity homeostasis. Whether GM-CSF plays a protective role against hepatocellular carcinoma (HCC) by regulating immunity and intestinal microecology is not completely understood. Orthotopic transplantation tumor models of HCC were established in mice by transfecting human GM-CSF sequences into a human HCC cell line using lentivirus. We measureed the absolute abundance of specific fecal bacterial communities using the absolute quantificative 16S rRNA amplicon sequencing technology. This study provides new insights into the therapeutic approaches for HCC.
