Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 28, 2022; 28(32): 4600-4619
Published online Aug 28, 2022. doi: 10.3748/wjg.v28.i32.4600
Sirolimus increases the anti-cancer effect of Huai Er by regulating hypoxia inducible factor-1α-mediated glycolysis in hepatocellular carcinoma
Lin Zhou, Yang Zhao, Li-Chao Pan, Jing Wang, Xian-Jie Shi, Guo-Sheng Du, Qiang He
Lin Zhou, Yang Zhao, Jing Wang, Qiang He, Department of Hepatobiliary and Pancreaticosplenic Surgery, Beijing ChaoYang Hospital, Capital Medical University, Beijing 100020, China
Li-Chao Pan, Xian-Jie Shi, Guo-Sheng Du, Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing 100853, China
Author contributions: Zhou L, Zhao Y, and Pan LC contributed equally to this work; Zhou L, Shi XJ, and He Q contributed to conception and design; Du GS, Shi XJ, and He Q contributed to administrative support; He Q and Du GS contributed to provision of study materials; Zhou L, Pan LC, and Wang J contributed to experimental manipulation; Zhao Y, Wang J, and Zhou L contributed to collection and assembly of data; Wang J and Zhao Y contributed to data analysis and interpretation; all authors contributed to manuscript writing and final approval.
Supported by the Natural Science Foundation of Capital Medical University, No. PYZ20014 and No. PYZ21074.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Beijing Chaoyang Hospital, No. 2021-1-19-3; and PLA General Hospital, No. S2108-013-01.
Informed consent statement: All study participants, or their legal guardians, provided written informed consent for personal and medical data collection prior to study enrolment.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: The data used and analysed in this study are included in the article or are available from the corresponding and first authors upon reasonable request.
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 Non Commercial (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: Guo-Sheng Du, MD, Professor, Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, No. 28 Fuxing Road, Haidian District, Beijing 100853, China. duguosheng309@126.com
Received: November 10, 2021
Peer-review started: November 10, 2021
First decision: January 9, 2022
Revised: January 11, 2022
Accepted: July 16, 2022
Article in press: July 16, 2022
Published online: August 28, 2022
Processing time: 289 Days and 0.8 Hours
ARTICLE HIGHLIGHTS
Research background

Hypoxic and high lactate environment further aggravates the aerobic glycolytic effect of cancer and promotes the proliferation and metastasis of liver cancer. Hypoxia-inducible factor 1α plays an important role in the Warburg effect.

Research motivation

We found in clinical practice that the combination of sirolimus (SRL) and Huai Er granules can prolong the survival time of liver transplant patients and delay tumor recurrence. The mechanism of such combination therapy is unclear.

Research objectives

To clarify the regulatory mechanism of SRL combined with Huaier intervention on the Warburg effect.

Research methods

In order to solve the scientific problems raised in this study, immunohistochemistry, cell culture, cell scratch and clone formation assays, and flow cytometry were used to analyze the changes of cell levels.

Research results

Hypoxia-mediated glycolysis was associated with poorly differentiation HCC and a lower prognosis. Hypoxic-induced HIF-1α promoted the growth of HepG2 and Huh7 cells, which was weakened with the treatment of SRL and Huai Er. SRL increased the anti-cancer effect of Huai Er, which reduced the promotion of hypoxia-induced HIF-1α on the Warburg effect by inhibiting the PI3K/Akt/mammalian target of rapamycin (mTOR)-HIF-1α and HIF-1α-phosphatase and tensin homolog deleted on chromosome ten (PTEN) signaling pathways in HCC.

Research conclusions

SRL increases the anti-cancer effect of Huai Er, which reduces the promotion of hypoxia-induced HIF-1α on the Warburg effect by inhibiting the PI3K/Akt/mTOR-HIF-1α and HIF-1α-PTEN signaling pathways in HCC.

Research perspectives

This study confirmed that SRL combined with Huai Er can downregulate the Warburg effect mediated by HIF-1α, laying a foundation for the combined treatment of HCC with traditional Chinese and western medicine.