Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 28, 2019; 25(16): 1936-1949
Published online Apr 28, 2019. doi: 10.3748/wjg.v25.i16.1936
Signal transducer and activator of transcription 3 promotes the Warburg effect possibly by inducing pyruvate kinase M2 phosphorylation in liver precancerous lesions
Yang-Hui Bi, Wen-Qi Han, Ruo-Fei Li, Yun-Jiao Wang, Zun-Shu Du, Xue-Jiang Wang, Ying Jiang
Yang-Hui Bi, Wen-Qi Han, Ruo-Fei Li, Yun-Jiao Wang, Zun-Shu Du, Xue-Jiang Wang, Ying Jiang, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Author contributions: Bi YH and Han WQ contributed equally to this work; Jiang Y and Wang XJ designed the research; Jiang Y, Bi YH, Han WQ, Li RF, Wang XJ, and Du ZS performed the research; Jiang Y contributed new reagents or analytic tools; Jiang Y, Bi YH, and Han WQ analyzed the data and wrote the paper; all of the authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81070319; the Beijing Natural Science Foundation of China, No. 7102013; and the Beijing Municipal Education Commission Research Program, China, No. KM201610025004.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Capital Medical University [IACUC protocol number: (AEEI-2016-118)].
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: The manuscript has no additional data 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 which 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: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Ying Jiang, PhD, Professor, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, No. 10, Xitoutiao, You An Men Wai, Beijing 100069, China. jiangy@ccmu.edu.cn
Telephone: +86-10-83911687
Received: January 27, 2019
Peer-review started: January 27, 2019
First decision: February 26, 2019
Revised: March 7, 2019
Accepted: March 24, 2019
Article in press: March 25, 2019
Published online: April 28, 2019
ARTICLE HIGHLIGHTS
Research background

Hepatocellular carcinoma (HCC) is the fifth common malignant tumor worldwide and has a poor prognosis. HCC is closely associated with the potential precancerous lesions. Early treatment at the precancerous stage could significantly prevent the occurrence of HCC. Signal transducer and activator of transcription 3 (STAT3) and pyruvate kinase M2 (PKM2) can be activated and enhance the Warburg effect in HCC. However, whether activation of STAT3 enhances the Warburg effect in liver precancerous lesions in rats, and the relationship between STAT3 and PKM2 remain unclear. Hence, clarifying the mechanism of liver precancerous lesion of HCC are very important.

Research motivation

Investigating the mechanism of STAT3 and the Warburg effect in liver precancerous lesions in rats may suggest potential molecular mechanisms of hepatocellular carcinogenesis, and further offer the potential for developing novel therapeutic strategies for HCC treatment.

Research objectives

To measure the expression of STAT3 and PKM2, and the Warburg effect in liver precancerous lesions in rats and in transformed WB-F344 cells, and to investigate the possible molecular mechanisms of STAT3 in liver precancerous lesions.

Research methods

The Solt-Farber model is an established hepatic precancerous animal model. The transformed WB-F344 cells were induced with N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) and hydrogen peroxide (H2O2). The contents of glucose and lactate in the tissue and culture medium of the cells were detected with a spectrophotometer. The protein levels were examined by Western blot and immunofluorescence.

Research results

Here, we provide the evidence that the Warburg effect was enhanced in liver precancerous lesions in rats, perhaps through high expression of PKM2 and p-STAT3 in activated oval cells. STAT3 activation promotes the Warburg effect by activating PKM2 in transformed WB-F344 cells induced with MNNG and H2O2.

Research conclusions

STAT3 activation promotes the Warburg effect by enhancing the phosphorylation of PKM2 in transformed WB-F344 cells. The Warburg effect, PKM2 and STAT3 expression were increased in liver precancerous lesions in rats.

Research perspectives

We have carried out some rat experiments and in vitro cell experiments, but further studies are needed to explore the mechanism of liver precancerous lesions. We also need to collect clinical samples for further validation. STAT3 and PKM2 may be potential diagnostic or therapeutic targets and used for clinical diagnosis and therapy in the future.