Analysis of Key Genes Regulating the Warburg Effect in Patients with Gastrointestinal Cancers and Selective Inhibition of This Metabolic Pathway in Liver Cancer Cells

Xinyue Zhang; Jinan Guo; Parham Jabbarzadeh Kaboli; Qijie Zhao; Shixin Xiang; Jing Shen; Yueshui Zhao; Fukuan Du; Xu Wu; Mingxing Li; Huijiao Ji; Xiao Yang; Zhangang Xiao; Qinglian Wen

doi:10.2147/OTT.S257944

Analysis of Key Genes Regulating the Warburg Effect in Patients with Gastrointestinal Cancers and Selective Inhibition of This Metabolic Pathway in Liver Cancer Cells

Onco Targets Ther. 2020 Jul 27:13:7295-7304. doi: 10.2147/OTT.S257944. eCollection 2020.

Authors

Xinyue Zhang^#^{1

2

3}, Jinan Guo^#^{4

5}, Parham Jabbarzadeh Kaboli^{2

6}, Qijie Zhao², Shixin Xiang², Jing Shen^{2

6}, Yueshui Zhao^{2

6}, Fukuan Du^{2

6}, Xu Wu^{2

6}, Mingxing Li^{2

6}, Huijiao Ji^{2

6}, Xiao Yang², Zhangang Xiao^{2

6}, Qinglian Wen^{1

3}

Affiliations

¹ Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China.
² Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People's Republic of China.
³ Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan, People's Republic of China.
⁴ The Department of Urology, The Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen Urology Minimally Invasive Engineering Center, Shenzhen, Guangdong, People's Republic of China.
⁵ Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen, Guangdong, People's Republic of China.
⁶ South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, People's Republic of China.

^# Contributed equally.

Abstract

Objective: The Warburg effect, also known as aerobic glycolysis, plays a dominant role in the development of gastrointestinal (GI) cancers. In this study, we analyzed the expression of key genes involved in the Warburg effect in GI cancers and investigated the effect of suppressing the Warburg effect in vitro in liver cancer cell lines.

Methods: The Cancer Genome Atlas (TCGA) RNA-Seq data were used to determine gene expression levels, which were analyzed with GraphPad Prism 7.00. Genetic alterations were queried with cBioPortal. The influence of the Warburg effect on liver cancer cell viability, migration and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity was determined by means of MTT, transwell and GAPDH activity assays.

Results: The levels of expression of genes associated with the Warburg effect were increased in tumors. To our knowledge, this is the first report of upregulated expression of CUEDC2, HMGB2, PFKFB4, PFKP and SIX1 in liver cancer. Clinically, overexpression of these genes was associated with significantly worse overall survival of liver cancer patients. In vitro, selective inhibition of GADPH suppressed the growth and metastasis of Huh-7, Bel7404 and Hep3B hepatocellular carcinoma cell lines.

Conclusion: The Warburg effect may play an important role in GI cancers, especially in liver cancer.

Keywords: GAPDH; Warburg effect; bioinformatics; gastrointestinal cancers; liver cancer.

Grants and funding

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81503093, 81602166, and 81672444), and by the Joint Funds of Southwest Medical University & Luzhou (2016LZXNYD-T01, 2017LZXNYD-Z05 and 2017LZXNYD-J09).