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. 2014 Mar 23;140(9):1451–1456. doi: 10.1007/s00432-014-1649-8

The role of miR-148a in gastric cancer

Jiazeng Xia 1,✉, Xiaoqiang Guo 1, Jiang Yan 1, Kaiyuan Deng 1
PMCID: PMC11823805  PMID: 24659367

Abstract

Purpose

Gastric cancer is one of the most common malignant diseases worldwide, although much progress has been achieved in recent years, the early diagnosis and treatment for gastric cancer are not yet satisfactory and, thus the prognosis is still poor. MicroRNAs (miRNAs) can regulate a variety of physiological and developmental processes, it has been revealed that many miRNAs contribute the initiation and progression of various cancers. MiR-148a is one of the most important miRNAs in gastric cancer, and the aim of this paper is to provide an overview of various roles of miR-148a in gastric cancer.

Methods and results

We searched studies in electronic databases. MiR-148a was down-regulated in gastric cancer tissues and cell lines, which was resulted from the hypermethylation in its promoter region. Furthermore, miR-148a could regulate several different target genes and pathways involving tumor proliferation, invasion and metastasis.

Conclusion

MiR-148a may serve as a novel biomarker for the diagnosis and as a new therapeutic target in gastric cancer.

Keywords: miR-148a, Gastric cancer, MicroRNA, Methylation

Introduction

Gastric cancer (GC) remains a major public health issue as the second leading cause of cancer related death and the fourth most common cancer worldwide, with an estimated one million new cases per year, approximately 50 % of cases occur in Eastern Asia (Ferlay et al. 2010). GC is typically diagnosed at advanced stage accompanied by extensive invasion and metastasis, successful therapeutic strategies are limited, and recurrence and metastasis are the biggest challenges during treatment (Shi and Zhou 2010). A deep understanding of the pathogenesis and biological features of GC has major importance and may tend to develop novel avenues for targeted therapy. Although Helicobacter pylori infection, gastrin levels, germline mutations, dietary factors and other chronic gastric conditions are all factors involved in the development of GC, but more and more studies have shown that GC originates from a sequential accumulation of molecular and genetic alterations to stomach epithelial cells (Yasui et al. 2011).

MicroRNAs (miRNAs) are noncoding RNAs of about 19–23 nucleotides that are not translated into proteins but regulate 60 % of coding genes by binding to mRNA molecules. In general, miRNAs are transcribed by RNA polymerase II into pri-miRNAs, which is cleaved in the nucleus by RNAse III Drosha into 70–100-nucleotides pre-miRNA (Lee et al. 2004). Pre-miRNA is mediated by the RNAse III Dicer to generate double-stranded RNAs approximately 22 nucleotides long and then undergo final maturation into a functional miRNA (Yi et al. 2003). There are more than 2,000 miRNAs registered in the ‘miRbase’ database (Rukov et al. 2013). Although the role of most miRNAs is still unclear, more and more studies have shown that they are involved in a wide variety of physiological processes including cell fate specification, proliferation, cell death as well as in diseases like cancers (Croce 2009; Iorio and Croce 2012).

Many miRNAs have been identified as oncogenes and tumor suppressors through altering the expression of target genes by both downregulation and upregulation, which are related to gene deletions, mutations, polymorphisms, promoter hypermethylation or histone acetylation as well as other mechanisms. Given that cancer is a complex genetic disease characterized by uncontrolled proliferation, migration, invasion and failure of apoptotic cell death, miRNAs may have different expression profiles in specific types of cancer. MiRNAs profiling can make a distinction among different tumors or between normal tissues and tumor tissues. For example, Chen et al. applied 2 different proprietary microarray platforms on primary gastric cancer tissue samples and identified 17 upregulated miRNAs and 12 downregulated miRNAs that were consistently deregulated in both microarray platforms. Eight miRNAs with greater than two-fold change were further validated using qRT-PCR in gastric and esophageal adenocarcinoma tissues, and the results revealed that miR-148a, miR-146b-5p, miR-375, miR-31 and miR-451 were significantly dysregulated in GC but not in esophageal adenocarcinoma, while dysregulation of miR-21 (upregulation) and miR-133b (downregulation) was detected in both GC and esophageal adenocarcinomas, and miR-200a was significantly decreased in GC but increased in esophageal adenocarcinomas (Chen et al. 2013). On the other hand, in the same cancer, some miRNAs may be upregulated and serve as oncogenes, while others may be downregulated thus serve as tumor suppressors (Ichikawa et al. 2012; Song and Ajani 2013). This deregulation of various miRNAs has been associated with tumor diagnosis and prognosis, indicating that they might be potential biomarker and therapeutic target in clinical application. In this article, we will focus on one of the downregulated miRNAs, miR-148a, review the current research regarding the role of miR-148a in GC, summarize the expression and regulation of miR-148a in GC, and discuss the potential use of miR-148a in the diagnosis, prognosis and treatment of GC.

miR-148a expression in GC

Several studies have shown that miR-148a was significantly downregulated in GC cell lines and in GC tissue samples compared to the adjacent normal gastric tissues (Chen et al. 2013; Zheng et al. 2011, 2014; Tchernitsa et al. 2010; Chen et al. 2010; Wang et al. 2013; Zhu et al. 2012; Sakamoto et al. 2014; Tseng et al. 2011). MiR-148a was found to be downregulated in different stages of GC by several microarray researches and further confirmed by qRT-PCR (Chen et al. 2013; Zheng et al. 2014; Tchernitsa et al. 2010; Sakamoto et al. 2014; Tseng et al. 2011). Even in early GC, miR-148a can also serve as a biomarker (Zheng et al. 2014). Zheng et al. examined miR-148a levels in 90 gastric cancer samples by qRT-PCR and analyzed the clinicopathologic significance of miR-148a expression, and the results turned out that miR-148a expression was suppressed by more than four-fold in gastric cancer compared with their corresponding nontumorous tissues, and the downregulated miR-148a was significantly associated with TNM stage and lymph node metastasis. Functionally, overexpression of miR-148a suppressed gastric cancer cell invasion and metastasis in vitro and lung metastasis formation in vivo (Zheng et al. 2011). Liu et al. found that low expression of miR-148a was also correlated with increased tumor size and advanced pT stage (Chen et al. 2010). Another study showed that low miR-148a levels were associated with lymph node metastasis, N stage and blood vessel invasion (Wang et al. 2013). Zhu et al. showed that downregulation of miR-148a in 84 % of 38 cases of GC tissues compared with their normal mucosae as well as in two GC cell lines BGC-823 and SGC-7901. Cell proliferation was suppressed in cell lines transfected with pre-miR-148a plasmid but no obvious change in apoptosis (Zhu et al. 2012). Using miRNA microarray analysis, Sakamoto et al. found six miRNAs which were downregulated in GC tissues, and miR-148a was the most downregulated one. Further evaluation showed that downregulation of miR-148a was significantly correlated with an advanced clinical stage, lymph node metastasis and poor clinical outcome, indicating that miR-148a was an independent prognosis marker in GC (Sakamoto et al. 2014). Tseng et al. (2011) also confirmed that miR-148a was significantly downregulated in GC tissues compared to normal tissues by both qRT-PCR and microarray methods, and high expression levels of miR-148a significantly correlated with reduction in distant metastasis, organ invasion and peritoneal invasion as well as higher 5-year overall survival rates in GC patients. Furthermore, GC cell lines transfected with miR-148a precursor and inhibitor could, respectively, reduce and increase cell growth, invasion, migration and adhesion. Taking together the fact that miR-148a was downregulated in GC tissues and cell lines and that lower expression level of miR-148a correlate with worse clinicopathologic characters in GC, strategies regarding the regulation of miR-148a expression might be used for the treatment of GC.

Circulating miR-148a in GC patients

Tumor-associated miRNAs in the plasma and serum are derived from the necrosis and the apoptosis of tumor cells as well as active secretion from tumor cells (Schwarzenbach et al. 2011). These cell-derived endogenous miRNAs are present in the blood in a remarkably stable state that is protected from endogenous RNase activity. In recent years, these miRNAs, like other molecules in the plasma and serum, have been stably detected and applied for the new biomarkers. Michell et al. (2008) first demonstrated that circulating miRNAs had the potential to be used for the diagnosis of patients with solid cancers. From then on, several groups have reported the use of circulating miRNAs as biomarkers in patients with GC (Tsujiura et al. 2010; Liu et al. 2011, 2012). The candidate miRNAs in these studies are mostly those upregulated in GC tissues, because the plasma levels of these miRNAs reflected the tumor levels and were significantly higher in GC patients than in normal controls. Whether circulating miR-148a could be used as a diagnosis biomarker for GC should be elucidated further. Interestingly, a recent research showed that serum concentration of miR-148a was closely associated with GC pN stage, patients with lymph node metastasis had higher serum levels of miR-148a, miR-21 and miR-146a than those without lymph node metastasis, indicating that miR-148a as well as miR-21 and miR-146a might be used for noninvasive biomarkers to predict lymph node metastasis in patients with GC (Kim et al. 2013).

miR-148a is silenced by promoter hypermethylation in GC

The occurrence of many diseases is related to the dysregulated gene expression resulting from genetic and epigenetic abnormalities. Epigenetic modifications regulate the gene expression without changing the DNA sequence. DNA methylation is an epigenetic modification which has been reported to result in inactivating the expression of many genes, including miRNAs (Braconi et al. 2010). Global patterns of DNA methylation are established and maintained by DNA methyltransferases (DNMTs): DNMT1, DNMT3A, DNMT3B and DNMT3L (Zhu et al. 2012). DNMT1 mediates the transfer of methyl groups from S-adenosylmethionine to the 5 position of cytosine bases in the dinucleotide sequence CpG (Herman and Baylin 2003). DNMT1 plays an important role in tumorigenesis and is abnormally expressed in many tumor types, including GC (Tennis et al. 2012; Cacan et al. 2014; Agarwal et al. 2013; Yang et al. 2011a).

Several studies have demonstrated that in GC miR-148a was inactivated by hypermethylation of DNA in the promoter region of its gene (Zhu et al. 2012; Sakamoto et al. 2014; Zuo et al. 2013). Zhu et al. demonstrated that, in GC tissues and cell lines, miR-148a was silenced by hypermethylation of its promoter region, which was mediated through DNMT1 overexpression. Their data showed that miR-148a expression was restored in GC cell lines when treated with 5-aza-dc, while knockdown of DNMT1 with siRNA reduced the methylation level of miR-148a thus significantly upregulated the expression of miR-148a, suggesting that DNMT1 has a critical role in regulating miR-148a expression through controlling methylation level of its promoter. Furthermore, the expression of DNMT1 protein was repressed after the restoration of miR-148a, suggesting that DNMT1 might be a target of miR-148a and that there might exist a miR-148a-DNMT1 circulating regulation in GC (Zhu et al. 2012). Interestingly, this circulating regulation mechanism between miR-148a and DNMT1 was also confirmed in breast cancer and in patients with lupus (Pan et al. 2010; Xu et al. 2013). Considering that miRNAs and their targets usually play roles through a network but not act as a single factor, further studies should be focused on other genes and noncoding RNAs that may also participating in the regulation.

Target genes of miR-148a in GC

Just like that one gene perhaps is targeted by different miRNAs, one miRNA may regulate diverse pathways and cause various phenotypes depending on the availability of a certain population of mRNA targets. A recently published study used online database to predict the plausible targets of miR-148a and their involvement in various signal pathways, and found that miR-148a may regulate several pathways in GC, such as ErbB, mTOR, MAPK, cell cycle, Jak-STAT, p53 and VEGF signaling pathways as well as the Wnt and TGF-beta pathways (Zheng et al. 2014). But usually, these computational target genes may have false-negative and false-positive results when compared to those results from laboratory techniques (Alexiou et al. 2009), such as microarray, luciferase reporter assays, qRT-PCR, western blots, immunoprecipitation and next-generation sequencing (Anders et al. 2012; Khorshid et al. 2011; Yang et al. 2011b). Recent years, several pathways, including DNMT1 as mentioned above, have been elucidated with these laboratory techniques to be regulated directly or indirectly by miR-148a in GC (Fig. 1).

Fig. 1.

Fig. 1

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Target genes in miR-148a in gastric cancer

Tseng et al. used a novel integrative network-based approach to identify active miRNAs and their potential functions, and the results suggested that miR-148a could directly regulate PAI-1, IFGB8, VAV2 and ITGAS which were involved in tumor cell growth, migration, adhesion, invasion and angiogenesis (Tseng et al. 2011).

Another study has demonstrated that SMAD2 was a direct and functional target gene of miR-148a, and overexpression of miR-148a could inhibit expression of SMAD2 and further downregulate vimentin expression and upregulate E-cadherin, suggesting that miR-148a suppressed epithelial-mesenchymal transition (EMT) and metastasis in GC (Wang et al. 2013).

ROCK1 is a potential promoter for tumor invasion and metastasis. A study has revealed that in GC tissues, there was an inverse correlation between miR-148a and ROCK1 expression, and overexpression of miR-148a in GC cells could reduce the expression of ROCK1. Moreover, luciferase assays confirmed that miR-148a could directly bind to the 3′ untranslated region of ROCK1 and knockdown of ROCK1 significantly inhibited GC cell migration and invasion. These data demonstrated that miR-148a could induce GC cell migration and metastasis by directly targeting ROCK1 (Zheng et al. 2011).

RUNX3 is a tumor suppressor involved both in the Wnt and in the TGF-beta signaling pathways which induce cell cycle arrest and apoptosis (Ito 2011). Our group has confirmed that miR-148a could indirectly target RUNX3 via DNMT1 in GC (Zuo et al. 2013). In addition, CCKRB (Chen et al. 2010), MMP7 (Sakamoto et al. 2014) and p27 (Guo et al. 2011) were also demonstrated to be targets of miR-148a in GC.

miR-148a interacts with other noncoding RNAs in GC

Interestingly, miR-148a can not only target those protein-coding genes, but also target noncoding RNAs. MiR-148a is a member of miR-148/152 family, which includes miR-148a, miR-148b and miR-152. Both miR-148a and miR-152 were downregulated in gastric cancer (Chen et al. 2010). A study revealed that there existed a novel miR-148a/152-DNMT1 regulatory circuit in breast cancer, which had similar downregulation of miR-148a and miR-152 as found in GC (Xu et al. 2013), indicating that there might be a similar regulatory relationship between miR-148a and miR-152 in GC.

Previous evidences have shown that, a long noncoding RNA (lncRNA), MEG3 is downregulated and related to prognosis in GC (Sun et al. 2014). More interestingly, our group recently demonstrated that miR-148a can regulate MEG3 through DNMT1 in GC (Yan et al. 2014). Our results showed that the suppression of miR-148a may contribute the downregulation of MEG3 by modulation of DNMT1, and overexpression of miR-148a could downregulate the expression of DNMT1 and induce the expression of MEG3, causing the inhibition of GC cell growth. The study enhances our understanding of how miRNAs interact with target genes and other noncoding RNAs in GC and may indicate additional potential targets for gastric cancer therapy.

Conclusions

MiR-148a has been found to be silenced by DNMT1 and serve as a tumor suppressor in GC. It can regulate several target genes and pathways involving tumor proliferation, invasion and metastasis. MiR-148a might be used as biomarker for GC diagnosis, progression, prognosis and potential therapeutic target. However, although great progress has been made in recent years, more efforts are needed to investigate the molecular mechanism and function of miR-148a before it can be used in clinical practice in the future.

Acknowledgments

This work was supported by Six Major Talent Summit of Jiangsu Province (2011-WSK-013).

Conflict of interest

The authors have no conflict of interest to declare.

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