Impact Factor 4.137 | CiteScore 4.28
More on impact ›

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01258

TIGAR promotes tumorigenesis and protects tumor cells from oxidative and metabolic stresses in gastric cancer

Zhenhua Liu1, Yue Wu2,  Yingqiu Zhang3, Menglang Yuan3, Xuelu Li3, Jiyue Gao3, Shanni Zhang4, Chengjuan Xing5, Huamin Qin5, Hongbo Zhao6 and  Zuowei Zhao7*
  • 1Department of Gastrointestinal Surgery, the Second Affiliated Hospital of Dalian Medical University, China
  • 2Institute of Cancer Stem Cell, Dalian Medical University, China
  • 3Institute of Cancer Stem Cell, Dalian Medical University, China
  • 4Dalian Maternal and Child Health Care Hospital, China
  • 5Department of Pathology, Second Affiliated Hospital of Dalian Medical University, China
  • 6Department of Gastrointestinal Surgery, Anyang Tumor Hospital, China
  • 7the second affiliated hospital of Dalian Medical University, China

Cancer cells adopt glycolysis to facilitate the generation of biosynthetic substrates demanded by cell proliferation and growth, and to adapt to stress conditions such as excessive reactive oxygen species accumulation. TIGAR (TP53-induced glycolysis and apoptosis regulator) is a fructose-2,6-bisphosphatase that is regulated by p53. TIGAR functions to inhibit glycolysis and promote antioxidative activities, which assists the generation of NADPH to maintain the levels of GSH and thus reduces intracellular reactive oxygen species. However, the functions of TIGAR in gastric cancer (GC) remain unclear. TIGAR expression levels were detected by immunoblotting and immunohistochemistry in gastric cancer samples, along with four established cell lines of GC. The functions of TIGAR were determined by utilizing shRNA-mediated knockdown experiments. The NADPH/ NADP+ ratio, reactive oxygen species, mitochondrial ATP production and phosphorus oxygen ratios were determined in TIGAR-depleted cells. Xenograft experiment was conducted with BALB/c nude mice. TIGAR was up-regulated compared with corresponding non-cancerous tissues in primary GCs. TIGAR knockdown significantly reduced cell proliferation and increased apoptosis. TIGAR protected cancer cells from oxidative stress-caused damages, but also glycolysis defects. TIGAR also increased the production of NADPH in gastric cancer cells. TIGAR knockdown led to increased reactive oxygen species production, elevated mitochondrial ATP production and phosphorus oxygen ratios. The prognosis of high TIGAR expression patients was significantly poorer than those with low TIGAR expression. Taken together, TIGAR exhibits oncogenic features in GC, which can be evaluated as a target for intervention in the treatment of GC.

Keywords: Apoptosis, cell cycle checkpoint, Glycolysis, Heterograft, Stomach neopl asms

Received: 29 Jul 2019; Accepted: 31 Oct 2019.

Copyright: © 2019 Liu, Wu, Zhang, Yuan, Li, Gao, Zhang, Xing, Qin, Zhao and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Zuowei Zhao, the second affiliated hospital of Dalian Medical University, Dalian, China,