Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Nov 15, 2021; 13(11): 1725-1740
Published online Nov 15, 2021. doi: 10.4251/wjgo.v13.i11.1725
Shuyu pills inhibit immune escape and enhance chemosensitization in hepatocellular carcinoma
Zhe Deng, Yong-Jie Teng, Qing Zhou, Zhao-Guang Ouyang, Yu-Xing Hu, Hong-Ping Long, Mei-Jie Hu, Si Mei, Feng-Xia Lin, Xin-Jun Dai, Bo-Yu Zhang, Ting Feng, Xue-Fei Tian
Zhe Deng, Xin-Jun Dai, Ting Feng, Xue-Fei Tian, College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
Yong-Jie Teng, Qing Zhou, Yu-Xing Hu, Mei-Jie Hu, The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
Zhao-Guang Ouyang, Department of Preventive Dentistry, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510132, Guangdong Province, China
Hong-Ping Long, Experiment Center of Medical Innovation, The First Hospital of Hunan University of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
Si Mei, Department of Physiology, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
Feng-Xia Lin, Department of Cardiology, Shenzhen Bao'an Traditional Chinese Medicine Hospital Group, The Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen 518133, Guangdong Province, China
Bo-Yu Zhang, College of Acupuncture and Massage, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
Author contributions: Deng Z, Teng YJ, Ouyang ZG, Hu YX, Hu MJ performed the experiments; Deng Z, Tian XF and Zhou Q designed and performed the study, conducted the statistical analysis and wrote the paper; Tian XF conceived and designed the study; Long HP performed high performance liquid mass spectrometry; Zhang BY processed the figures of the article; Mei S, Lin FX, Dai XJ, and Feng T reviewed and edited the manuscript; all authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy and integrity of any part of the work are appropriately investigated and resolved.
Supported by National Natural Science Foundation of China, No. U20A20408, and No. 82074450; Special Natural Science Fund for the Construction of an Innovative Province in Hunan Province, No. S2020JJMSXM1250; the Natural Science Foundation of Hunan Province, No. 2020JJ4066; Hunan Province "domestic first-class cultivation discipline" Integrated Traditional Chinese and Western medicine open fund project, No. 2018ZXYJH28 and No. 2020ZXYJH35.
Institutional animal care and use committee statement: This study was reviewed and approved by the Ethics Review Committee of Experimental Animal Welfare at the Central South University in Changsha, China.
Conflict-of-interest statement: All the authors declare that they have no competing interests.
Data sharing statement: Dataset available from the corresponding author at 003640@hnucm.edu.cn. Participants gave informed consent for data sharing.
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: Xue-Fei Tian, PhD, Professor, College of Integrated Chinese and Western Medicine, Hunan Key Laboratory of Translational Research in Formulas and Zheng of Traditional Chinese Medicine, Hunan University of Chinese Medicine, No. 300 Xueshi Road, Yuelu District, Changsha 410208, Hunan Province, China. 003640@hnucm.edu.cn
Received: April 19, 2021
Peer-review started: April 19, 2021
First decision: July 16, 2021
Revised: July 18, 2021
Accepted: September 14, 2021
Article in press: September 14, 2021
Published online: November 15, 2021
ARTICLE HIGHLIGHTS
Research background

Hepatocellular carcinoma (HCC) is characterized by dysregulation of the immune microenvironment and the development of chemoresistance. The latest research shows that the simultaneous inhibition of hypoxia-inducible factor-1 alpha (HIF-1α) and programmed cell death protein 1 (PD-1) has the potential to enhance the hosts antitumour immunity. Moreover, inhibition of the PD-1/programmed cell death 1 ligand 1 (PD-L1) axis may mitigate tumour chemoresistance.

Research motivation

Shuyu pills (SYPs) contain immunity-enhancing and antitumour components, making them a potential HCC treatment. The motivation of this research was to study the effect and mechanism of SYPs on HCC.

Research objectives

To investigate the efficacy of SYPs for HCC treatment via simultaneous HIF-1α and PD-L1 inhibition and the mechanism involved.

Research methods

The subcutaneous xenograft tumours model was established in BALB/c nude mice. The male mice (male, 5 weeks old; n = 24) were then randomly divided into the four groups (n = 6): Control group (0.9% normal saline), SYP group (200 mg/kg), SYP + cisplatin (DDP) group (200 mg/kg + 5 mg/kg weekly via intraperitoneal injection), and DDP group (5 mg/kg weekly via intraperitoneal injection). The tumour volumes and body weights of the mice were measured every 2 d. The mice were euthanized by cervical dislocation after 14 d of continuous treatment, and the xenograft tissues were excised and weighed. The western blot assay was used to measure the protein expression of HIF-1α, PD-1, PD-L1, CD4+ T cells, and CD8+ T cells in the HCC tumours from the mice. Quantitative reverse transcription polymerase chain reaction a was used for the real-time quantitative detection of PD-1, PD-L1, and HIF-1α mRNA expression. The immunofluorescence assay was conducted to examine the expression of CD4+ T cells and CD8+ T cells.

Research results

Compared with the mice in the control group, those in the SYP and SYP + DDP groups had lower tumour volumes and tumour weights. Moreover, the protein and mRNA expressions of the oncogene HIF-1α and that of the negative immunomodulatory factors PD-1 and PD-L1 were decreased in both the SYP and SYP + DDP groups, with the decrease effects being more prominent in the SYP + DDP group than in the SYP group. Additionally, the quantitative and protein expressions of CD4+ T cells and CD8+ T cells were simultaneously upregulated in the SYP + DDP group, whereas only the expressions of CD4+ T cells were upregulated in the SYP group. Finally, the expression of HIF-1α was found to be positively correlated with that of PD-1/PD-L1 and negatively correlated with the expression of the CD4+ T cells and CD8+ T cells.

Research conclusions

SYPs inhibit immune escape and enhance chemosensitization in HCC via simultaneous inhibition of HIF-1α and PD-L1, thus inhibiting the growth of subcutaneous xenograft tumours with HCC.

Research perspectives

SYPs inhibit immune escape and enhance chemosensitization in HCC. It is a potential adjuvant drug for the treatment of HCC.