Oxidative Stress Upregulates PDCD4 Expression in Patients with Gastric Cancer via miR-21

Abstract

Reactive oxygen species (ROS) plays a key role in carcinogenesis by aberrantly inducing signaling networks that initiatiate tumorigenesis and stimulate tumor progression. MicroRNAs (miRNAs) comprise a novel class of endogenous, small, noncoding RNAs that negatively regulate approximately 30% of the genes in a cell via degradation or translational inhibition of their target mRNAs. However, the effects of ROS on miRNAs expression and the role of miRNAs in ROS-mediated injury on carcinogenesis are uncertain. Using UV spectrophotometry and enzyme-linked immunosorbent assay (ELISA), we examined tissues from human gastric cancers and tissues adjascent to gastric cancer and normal gastric tissues and found that total anti-oxidation competence (T-AOC), superoxide dismutase (SOD) and catalase (CAT) concentrations were lower in gastric cancer patients compared to the control subjects, while the concentrations of DNA oxidative damage product 8-oxo-deoxyguanosine (8-OHdG) was higher. To determine the potential role of miRNA in gastric carcinogenesis, real-time quantitative polymerase chain reaction (QPCR) analysis was performed. We found that human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) mRNA and miR-21 expression were significantly upregulated in gastric cancer tissues than in the adjacent normal gastric tissues. Furthermore, the expression of programmed cell death 4 protein (PDCD4) in gastric cancer tissues was significantly lower than in adjacent normal gastric tissues. The expression of miR-21 and PDCD4 was highly correlated with the degree of differentiation, tumor staging, local lymphatic node metastasis and remote metastasis. Expression of miR-21 was negatively correlated with T-AOC, SOD and CAT, but positively correlated with 8-OHdG and hOGG1mRNA. In addition, the relative expression of PDCD4 was negatively correlated with miR-21. These results suggest that the defensive balance of oxidation and antioxidant system in patients with GC was impaired, resulting in enhanced oxidative tissue injury, which may directly contribute to gastric carcinogenesis. Thus we conclude that ROS promotes gastric carcinogenesis via upregulating miR-21 expression which in turn down-regulates the expression of PDCD4 in gastric cancer cells.

Significance of microRNA 21 in gastric cancer

“…miR-21 expressions was upregulated in gastric cancer tissues than in the adjacent normal gastric tissues. Moreover, expression of PDCD4 in gastric cancer tissues was lower than in adjacent normal gastric tissues [36]. The expression of miR-21 and PDCD4 varied with the degree of gastric cancer differentiation, tumour staging, local lymphatic node metastasis and remote metastasis.…”

“…Down regulation of mesenchymal markers by miR-21 expectedly suppress the cell proliferation, survival, and invasion of gastric cancer [30]. In vivo studies further revealed that tissues from human gastric cancer showed reduced concentration in anti-oxidation competence (T-AOC), superoxide dismutase (SOD) and catalase (CAT) levels compared to control subjects [36]. miR-21 expressions was upregulated in gastric cancer tissues than in the adjacent normal gastric tissues.…”

Hsa-let-7g miRNA regulates the anti-tumor effects of gastric cancer cells under oxidative stress through the expression of DDR genes

“…Aberrant miRNA-21 was found under oxidative stress in GC tissues and GC cells. Further study revealed oxidative stress promoted gastric carcinogenesis according to upregulating miR-21 expression (Tu et al, 2014). Excessive ROS induced by macrophages stimulated the promotion of GC growth according to suppression of miR-328 (Ishimoto et al, 2014).…”

Long-Term Vitamin D Supplementation and the Effects on Recurrence and Metabolic Status of Cervical Intraepithelial Neoplasia Grade 2 or 3: A Randomized, Double-Blind, Placebo-Controlled Trial

“…Supplementation with 50,000 IU vitamin D3 every 14 days for 16 weeks among adult patients with nonalcoholic fatty liver disease did not influence TAC concentrations [42]. Increased inflammatory cytokines and oxidative stress contribute to carcinogenesis through increased production of reactive oxygen species, cell proliferation, and secreting immune suppressors [5-6, 43]. Therefore, vitamin D intake due to its anti-inflammatory and antioxidative actions may be useful to decrease CIN2/3 complications.…”