The putative tumor suppressor microRNA-497 modulates gastric cancer cell proliferation and invasion by repressing eIF4E
Introduction
MicroRNAs (miRNAs) are a class of endogenous non-coding RNAs of 19–25 nucleotides in length that suppress protein expression through base pairing with the 3′-untranslated region (3′-UTR) [1]. Mounting studies have documented a functional contribution of specific miRNAs in diverse biological processes [2], [3]. In addition, miRNAs have been discovered to have a role in progression and metastasis of human cancers recently [4], [5].
Gastric cancer (GC), one of the most common malignancies, ranks the second highest in the mortality rate worldwide [6]. The development of GC is a multistep process with accumulation of genetic and epigenetic changes. A growing body of evidence indicates that aberrant expression of miRNAs is involved in the progression of GC [7], [8]. MiRNAs that deregulated in GC have been identified as modulators of cell growth, apoptosis, migration, and invasion [9], [10]. A previous study indicated that miR-497 was down-regulated in GC [11]. However, the underlying mechanism of miR-497 in GC was unexplored.
Eukaryotic translation initiation factor 4E (eIF4E), a key player in translational control, has been found to contribute to tumor occurrence and development [12], [13], [14]. Over-expression of eIF4E results in the enhanced expression of various oncogenes, such as cyclin D1, VEGF, and MMP-9 [15]. Although eIF4E control of the translation of many oncogenes has been well documented, the upstream regulation of eIF4E itself is seldom reported.
In the present study, we found that low expression of miR-497 was associated with poor prognostic phenotype of GC. Furthermore, we identify that miR-497 can regulate the proliferation and invasion of GC cells by targeting directly the eIF4E gene.
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Cell lines and patient samples
Human GC cell lines and immortalized normal gastric mucosal epithelial cell line (GES-1) were purchased from the Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences (Shanghai, China). All cell lines were maintained in a humid wet atmosphere containing 5%CO2 at 37 °C in RPMI-1640 medium supplemented with 10% newborn bovine serum, 100 U/mL penicillin, and 100 mg/mL streptomycin. GC tissues were obtained from cancer center of Guangzhou Medical University. All GC specimens
Lower levels of miR-497 are frequently detected in GC tissues and associates with poorer overall survival of GC patients
Real-time PCR was performed to examine the expression levels of miR-497 in 36 pairs of GC and adjacent non-neoplastic tissues. As shown in Fig. 1 A, the expression levels of miR-497 were significantly decreased in GC tissues compared to adjacent non-neoplastic tissues (P < 0.05). The in situ hybridization assay also showed that miR-497 was down-regulated in GC tissues when compared with the non-neoplastic tissues (Fig. 1B).We further found that the expression level of miR-497 was lower in GC cell
Discussion
Despite the advancements in treatment options, improvements in GC patient survival have been limited owing to lack of early detection. Biomarkers to improve GC diagnosis, prognosis and prediction of treatment response therefore represent opportunities to improve patient outcome. In recent years, investigation of epigenetic biomarkers such as miRNA expression, have implicated that these alterations may be enticing translational biomarker candidates in GC. In the present study, we sought to
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