Aberrant expression of microRNAs in gastric cancer and biological significance of miR-574-3p

Abstract

The discovery of microRNAs (miRNAs) provides a new and powerful tool for studying the mechanisms, diagnosis and treatments of cancer. In this study, we employed AFFX miRNA expression chips to search for miRNAs that may be aberrantly expressed in gastric cancer tissues and to investigate the potential roles that miRNAs may play in the development and progression of gastric cancer. 14 miRNAs were found to be down-regulated and 2 miRNAs up-regulated in gastric cancer tissues compared to the normal gastric tissues. Among the aberrantly expressed miRNAs, miR-574-3p was selected to further study its expression features and functional roles. Interestingly, the reduced expression of miR-574-3p occurred mainly in the early stages of gastric cancer or in cancers with high level of differentiation, suggesting that it can be used as a marker for a mild case of gastric cancer. Functional study revealed that cell proliferation, migration and invasion were significantly inhibited in miR-574-3p-transfected gastric cancer SGC7901 cells. Computational prediction and experimental validation suggest that Cullin2 may be one of the targets of miR-574-3p. Overall our study suggests that the aberrantly expressed miRNAs may play regulatory and functional roles in the development and progression of gastric cancer.

Introduction

Cancer is a polygenic disease processing in many steps, and many genes have been found to be involved in the formation and progression of cancer. Gene alterations play important roles in uncontrollable proliferation, apoptosis evasion, angiogenesis, metastasis and invasion of cancer [1], [2], [3], [4]. However, the mechanisms of controlling the expression of the genes are still not fully understood. The discovery of microRNA provides a powerful tool for studying the mechanisms, diagnosis and treatments of cancers [5], [6].

MicroRNAs (miRNAs), approximately 19–24 nucleotides in length, are evolutionarily conserved small single-stranded non-coding RNA molecules. It was reported that more than 60% of human protein-coding genes have been under selective pressure to maintain their pairing with miRNAs [7]. They work mainly at post-transcriptional level by binding to the sequences in the 3′ untranslated regions (3′UTR) of their targeted mRNAs resulting in translational repression or gene silencing [7], [8], [9]. So far, the regions encoding some miRNAs have been found to be located in cancer-associated genomic regions or at fragile genomic sites [10]. MiRNAs are involved in regulation of wide array of biological processes, such as cell proliferation, differentiation and apoptosis [11], [12]. These processes are deregulated during the development and progress of a cancer, which may be associated with abnormal changes of miRNA. Indeed, aberrant expressions of miRNAs have been studied in several types of human cancers, including lung [13], colon [14], breast [15], prostate [16], hepatocellular [17] and ovarian [18] cancers. They may play roles in the development and progression of cancers similar to those played by oncogenes or tumor suppressor genes [19], [20].

Although aberrant expression of miRNAs in gastric cancer has been reported recently, the results are various between groups [21], [22], [23], [24]. In addition, the function roles of these aberrant expressed miRNAs in gastric cancer remain largely unknown and their mRNA targets are barely studied. In order to gain more information on this issue, we employed AFFX miRNA expression chips to study the aberrant expressions of miRNAs and quantitative real-time PCR to identify and confirm miRNAs with aberrant expressions in gastric cancer. Among the aberrantly expressed miRNAs, we chose miR-574-3p to further study their functional roles concerning proliferation, migration and invasion of gastric cancer cells. We also computationally predicted and experimentally validated the target of miR-574-3p.