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Microrna and Signaling Pathways in Gastric Cancer Cancer Gene Therapy (2014) 21, 305–316 & 2014 Nature America, Inc. All rights reserved 0929-1903/14 www.nature.com/cgt REVIEW MicroRNA and signaling pathways in gastric cancer Z Zhang1,ZLi1,YLi2 and A Zang1 MicroRNAs (miRNAs) function as either oncogenes or tumor suppressors by inhibiting the expression of target genes, some of which are either directly or indirectly involved with canonical signaling pathways. The relationship between miRNAs and signaling pathways in gastric cancer is extremely complicated. In this paper, we determined the pathogenic mechanism of gastric cancer related to miRNA expression based on recent high-quality studies and then clarified the regulation network of miRNA expression and the correlated functions of these miRNAs during the progression of gastric cancer. We try to illustrate the correlation between the expression of miRNAs and outcomes of patients with gastric cancer. Understanding this will allow us to take a big step forward in the treatment of gastric cancer. Cancer Gene Therapy (2014) 21, 305–316; doi:10.1038/cgt.2014.37; published online 25 July 2014 INTRODUCTION THE miRNA BIOGENESIS AND FUNCTION Gastric cancer is the fourth most common cancer and the second The miRNAs are small noncoding RNAs that are B22 nucleotides leading cause of cancer-related death in the world.1 There are in length. To date, more than 2000 miRNAs have been identified in B1 million new patients diagnosed with gastric cancer every humans. In the nucleus, a primary miRNA of several kilobases is year.2 Gastrectomy is the mainstay treatment for gastric cancer; transcribed from the miRNA gene by RNA polymerase II/III.8,9 After however, early diagnosis is very difficult in clinics and the pro- transcription, the ribonuclease enzyme Drosha, coupled with its gnosis for advanced-stage patients is still very poor.1 There will be binding partner DGCR8, excises one or more B70-nucleotide a significant improvement in the diagnosis and treatment of stem-loop structures from the primary miRNA to form precursor gastric cancer if the relationships between oncogenesis, develop- miRNA.10 The precursor miRNA is then transported into the ment and prognosis are much better understood. cytoplasm by the Ran-GTP-dependent nuclear export factor, The complex interactions that take place among different Exportin-5.11 In the cytoplasm, Dicer processes the precursor etiological factors lead to genetic and epigenetic alterations of miRNA and generates a B22-nucleotide RNA duplex that contains proto-oncogenes and tumor-suppressor genes; a basic paradigm both the mature miRNA strand and its anti-strand.12 The mature underlying the pathogenesis of any cancer. Dysregulation of these stranded miRNA is incorporated into the RNA-induced silenc- genes results in abnormal function or expression of oncogenic ing complex that targets complementary sequences in the and tumor-suppressor proteins. Accumulating evidence indicates 30-untranslated region of mRNAs, thereby functioning as a means that microRNAs (miRNAs) are involved in important biological to cleave mRNA or inhibit its translational function.13,14 Afterward, processes related to apoptosis, proliferation, differentiation, the complementary strand is usually rapidly degraded15 (Figure 1). metastasis, angiogenesis and the immune response, dysregulation of which is crucial to cancer initiation, progression and treatment outcomes. Expression of miRNAs has been shown to be related to DYSREGULATED miRNAs IN GASTRIC CANCER gastric cancer as well as other cancers and plays important roles in There are an increasing number of studies demonstrating the regulating cancer-related genes.3,4 overexpression or downregulation of specific miRNAs in gastric The miRNAs act as posttranscriptional regulators of gene cancer, and these are listed in Table 1. There have been many studies expression that could regulate 430% of the protein-coding genes regarding miRNA functions in gastric cancer. Some miRNAs exhibit in the human genome.5 This class of RNAs was identified through downregulation as tumor suppressors (listed in Table 2), whereas investigation of Caenorhabditis elegans.6,7 Up till now, 1872 pre- others exhibit upregulation as oncogenes (listed in Table 3). cursors and 2578 mature forms of human miRNAs have been Furthermore, some miRNAs have displayed conflicting functions in discovered in accordance with the publication of miRBase version different studies (listed in Table 4), thereby indicating that more 20.0 (http://www.mirbase.org/). It is strongly believed that the research is needed. amount of miRNAs and the ways in which they function are much more complex than expected. We try to determine the progress of gastric cancer research THE miRNAs AND SIGNALING PATHWAYS IN GASTRIC CANCER related to miRNA expression based on studies performed in In the process of tumorigenesis and the development of gastric recent years and reviews of the regulation network and corre- cancer, miRNAs function as either oncogenes or tumor suppres- lated functions of these miRNAs. A better understanding of sors by inhibiting the expression of target genes, some of which miRNAs in gastric cancer may be achieved through the review are involved in canonical signaling pathways either directly or of this literature that will thus give rise to new avenues of indirectly. The results of recent studies regarding these activities research. are reviewed herein. 1Department of Oncological Surgery, Affiliated Hospital of Hebei University, Baoding, China and 2Department of Gastric Cancer, Fourth Hospital of Hebei Medical University, Shijiazhuang, China. Correspondence: Dr A Zang, Department of Oncological Surgery, Affiliated Hospital of Hebei University, 212, Yuhua East Road, Boding 071000, China. E-mail: [email protected] Received 20 February 2014; revised 19 June 2014; accepted 20 June 2014; published online 25 July 2014 MiRNA and signaling pathways in gastric cancer Z Zhang et al 306 Figure 1. Mechanism of microRNA action. pre-miRNA, precursor microRNA; pri-miRNA, primary microRNA; RISC, RNA-induced silencing complex. PI3K/Akt pathway Expression of MIF has been shown to be targeted by miRNA- The phosphatidylinositide 3-kinase (PI3K)/Akt pathway has been 451, the expression of which is downregulated in gastric cancer. implicated in cancer since the discovery of its enzymatic activity Restoration of miRNA-451 expression downregulates MIF and associated with viral oncoproteins 20 years ago. However, in the decreases expression of reporter genes with MIF target sequences past 10 years, it has become apparent that this pathway is one of in gastric cancer cells that is accompanied by a reduction in cell proliferation and an enhancement of cell death in response to the most frequently mutated pathways in all spontaneous human 31 tumors. PI3Ks belong to a conserved family of lipid kinases that irradiation. MiRNA-375 suppresses the PI3K/Akt pathway phosphorylate the 30-hydroxyl group of phosphoinositides.133 through direct targeting of PDK1, a kinase that phosphorylates There are three classes of PI3Ks grouped according to their sub- Akt. This is yet another miRNA that regulates the activity of the strate preference and sequence homology, but only class IA PI3Ks PI3K/Akt pathway. Ectopic expression of miRNA-375 substantially reduces cell viability through induction of the caspase-dependent are implicated in human cancers. The most well-characterized apoptotic pathway23; microarray analysis has revealed that product of this reaction is phosphatidylinositol-3,4,5-trisphosphate miRNA-375 is one of the most downregulated miRNAs in gastric or PIP3, a critical second messenger that recruits AKT for activation 134 cancer. Finally, other research has indicated that miRNA-143 is of growth, proliferation and survival signaling. PIP3 is negatively involved in the regulation of cell function through the PI3K/Akt regulated through dephosphorylation by the tumor-suppressor pathway because its target gene is Akt itself.35 phosphatase and tensin homolog (PTEN). Class IA PI3Ks are heterodimers comprising a regulatory subunit (p85a, p55a, p50a,p85b, p55g) and a catalytic subunit (p110a, p110b, p110d) Ras/Raf/MEK/ERK pathway 135 and are activated downstream of receptor tyrosine kinases. The Ras/Raf/MEK/extracellular-signal-regulated kinase (ERK) path- PTEN is a tumor-suppressor gene and its role in tumor biology is 136 way is another important pathway that plays a fundamental role well characterized. Inactivation of PTEN leads to the activation in the regulation of cell proliferation and survival as well as in of AKT through accumulation of PIP3. Moreover, pAkt is a crucial human tumorigenesis. The Ras/Raf/MEK/ERK pathway is a central protein involved in the regulation of cell cycle progression, cell signal transduction pathway that transmits signals from multiple survival, apoptosis, invasion and radiosensitivity. The PTEN gene is cell surface receptors to transcription factors in the nucleus.138 an important functional target of the miRNA-221/222 cluster in This pathway is frequently referred to as the MAP kinase pathway gastric cancer cells. Modulation of miRNA-221/222 expression by as MAPK stands for mitogen-activated protein kinase, thereby antisense or overexpression strategies directly affects PTEN indicating that this pathway can be stimulated by mitogens, cyto- expression.89 PTEN is also one of the target genes of miRNA-21 kines and growth factors. The pathway is activated by membrane that increases the proliferation and invasion of gastric cancer translocation
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