دانلود رایگان مقاله انگلیسی از کار انداختن پروکرسیردوکسین 2 توسط گسترش دهنده متیلاسیون برای مهاجرت و بقای سلول های سرطانی معده - NCBI 2018

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.

DISCUSSION

Gastric cancer is distinctive in terms of tumor heterogeneity, which makes it difficult to predict recurrence and metastasis.3 It commonly metastasizes to the liver, peritoneum, lung and bone. The median survival time of patients with metastatic gastric cancer does not exceed 6 months, and the survival period is shorter for patients who are aged ⩾60 years.26 Currently, there are no effective therapeutics available on the drug market for inhibiting gastric cancer metastasis.

It has been well proven that cancer cells exhibit higher ROS levels than normal healthy cells. In other words, they are more susceptible to elevated ROS, which leads to cell death; thus the expression of endogenous antioxidant enzymes is unusually high.4 Nonetheless, it is noteworthy that PrxII expression has often been observed to be silenced via CpG methylation in some cancers.11,14,15 As an example, we have shown that PrxII silencing in melanoma confers a metastatic benefit by promoting cell migration.9 In this study, we showed for the first time that the PrxII promoter is selectively methylated in some gastric cancer cell types. Although the underlying mechanism for the initiation of DNA methylation at the PrxII promoter has yet to be fully elucidated, we found that DNMT1 is responsible for the CpG methylation in the PrxII promoter region that regulates PrxII expression. Given that PrxII is a major ROS scavenger in cancer cells, downregulation of its expression is likely to be the main cause for the elevation in ROS levels. Because ROS are known to upregulate DNMT expression and activity,27 we propose a positive feed-forward regulatory loop where high ROS levels due to the silencing of PrxII could affect the DNMT status in cells, which may in turn elicit active gene silencing in gastric cancer cells.