Reduced microRNA-218 expression is associated with high nuclear factor kappa B activation in gastric cancer.
BACKGROUND
Poor expression of microRNAs (miRs) reportedly plays an important role in gastric carcinogenesis. Large-scale microarray assays have indicated that there is significant down-regulation of miR-218 in gastric cancer. miR-218 also was decreased specifically in human papillomavirus-positive cell lines, cervical lesions, and cervical cancer tissues and in bronchial airway epithelium in smokers. However, its role in carcinogenesis remains unclear, especially in Helicobacter pylori (H. pylori)-associated gastric cancer.


METHODS
miR-218 levels were evaluated in 20 noncardia gastric cancer tissues, in 10 H. pylori-infected and 8 uninfected normal gastric biopsies, and in the human gastric epithelial cancer cell line AGS using TaqMan quantitative real-time polymerase chain reaction analysis. Pre-miR-218 and anti-miR-218 inhibitors were used to examine the effects of miR-218 expression on cell proliferation and apoptosis. A luciferase reporter assay was used to examine the potential target genes and related pathways.


RESULTS
miR-218 expression was reduced significantly in gastric cancer tissues, in H. pylori-infected gastric mucosa, and in H. pylori-infected AGS cells. Overexpression of miR-218 inhibited cell proliferation and increased apoptosis in vitro. Epidermal growth factor receptor-coamplified and overexpressed protein (ECOP), which regulates nuclear factor kappa B (NF-kappaB) transcriptional activity and is associated with apoptotic response, was a direct target of miR-218. Overexpression of miR-218 also inhibited NF-kappaB transcriptional activation and transcription of cyclooxygenase -2, a proliferative gene regulated by NF-kappaB.


CONCLUSIONS
H. pylori infection resulted in a decrease in miR-218 expression. The down-regulation of miR-218 has the potential to increase carcinogenesis by losing control of its targets, and it may be correlated with the high transcriptional activity of NF-kappaB that results from H. pylori infection.
Gao
Caiping
C
Department of Gastroenterology, Shanghai Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Zhang
Zhiyu
Z
Liu
Wenzhong
W
Xiao
Shudong
S
Gu
Weiqi
W
Lu
Hong
H
D000230:Adenocarcinoma / Q000235:genetics*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000235:genetics; D015536:Down-Regulation; D066246:ErbB Receptors; D005753:Gastric Mucosa / Q000378:metabolism / Q000382:microbiology; D016481:Helicobacter Infections / Q000235:genetics; D016480:Helicobacter pylori; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
C547471:MIRN218 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D014157:Transcription Factors; C500380:VOPP1 protein, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors