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Abstract
Peroxiredoxin (Prx), a family of ubiquitous thiol peroxidases, functions as a redox signaling regulator that controls cellular H2O2 in mammalian cells and has recently received attention for being overexpressed in various cancer types. In this study, we show that Prx type II (PrxII) is rather silenced in gastric cancer cells. PrxII expression is severely downregulated in 9 out of the 28 gastric cancer cell lines. Strikingly, PrxII expression is completely lost in three cell lines, MKN28, MKN74 and SNU484. Loss of PrxII expression is due to DNA methyltransferase 1-dependent methylation at the promoter region of the PrxII gene. Restoration of PrxII expression using a retroviral system markedly reduces the colony-forming ability and migratory activity of both MKN28 and SNU484 cells by inhibiting Src kinase. Mechanistically, PrxII peroxidase activity is essential for regulating gastric cancer cell migration. Bioinformatics analysis from The Cancer Genome Atlas stomach cancer data (STAD) revealed significantly low PrxII expression in gastric cancer patients and a negative correlation between PrxII expression and methylation levels. More importantly, low PrxII expression also strongly correlates with poor survival in cancer patients. Thus our study suggests that PrxII may be the first thiol peroxidase that simultaneously regulates both survival and metastasis in gastric cancer cells with high clinical relevance.
Highlights
Gastric cancer is a leading cause of death worldwide, accounting for nearly 1 000 000 new cases annually and 4700 000 deaths in 2014
PrxII expression is silenced in gastric cancer cells by aberrant promoter methylation Protein levels of cytosolic 2-Cys Prxs, PrxI and PrxII were examined in 28 gastric cancer cell lines using specific antibodies
The data indicated that both protein and mRNA expression of PrxII were reduced in some gastric cancer cells
Summary
Gastric cancer is a leading cause of death worldwide, accounting for nearly 1 000 000 new cases annually and 4700 000 deaths in 2014. An estimation of 26 370 diagnosed cases of gastric cancer and eventually 10 730 deaths were reported in the United States in 2016.1,2 In most cases, gastric cancer treatment relies on gastrectomy and chemotherapy. Due to heterogeneity, gastric cancer recurrence rates are relatively high, and re-resection is no longer an available option for patients with metastatic cases.[3] therapeutics targeting gastric cancer cell metastasis are of clinical significance. Reactive oxygen species (ROS), including hydrogen peroxide (H2O2) and superoxide anion (O2 − ), are generated during cellular metabolism. Excess amounts of ROS damage cellular macromolecules, such as proteins, DNA and membrane lipids.[4]
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