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Micrornas in Tumorigenesis, Metastasis, Diagnosis and Prognosis of Gastric Cancer

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Micrornas in Tumorigenesis, Metastasis, Diagnosis and Prognosis of Gastric Cancer Cancer Gene Therapy (2015) 22, 291–301 © 2015 Nature America, Inc. All rights reserved 0929-1903/15 www.nature.com/cgt REVIEW MicroRNAs in tumorigenesis, metastasis, diagnosis and prognosis of gastric cancer C Jiang1, X Chen2, M Alattar3,JWei4 and H Liu5 MicroRNAs (miRNAs), which are small single-stranded RNA molecules composed of 18–23 nucleotides, act as oncogenes or tumor suppressor genes playing important roles in tumor formation, infiltration and metastasis. Subsequently, miRNAs expression contributes to cancer diagnosis and prognosis. Gastric cancer currently has high morbidity and mortality among all malignant tumors, yet it lacks early specific diagnostic markers and effective treatments. In gastric cancer, many studies have detected abnormal expression forms of miRNAs and confirmed their involvement in its tumorigenesis, progression, invasion and metastasis. They may become valuable diagnostic markers and therapeutic targets for gastric cancer. Studying the role of miRNAs in gastric cancer and its relationship with diagnostic and prognostic parameters might help to improve the sensitivity of diagnosis as well as the efficacy of gastric cancer treatment. This review aims to highlight the advancements which might provide new methods for early clinical diagnosis and effective therapeutic options, along with predict response to treatment for gastric cancer. Cancer Gene Therapy (2015) 22, 291–301; doi:10.1038/cgt.2015.19; published online 22 May 2015 Gastric cancer is the most common gastrointestinal malignant act as a tumor suppressor, whereas targeting tumor suppressor tumor which poses a serious threat to human health. According genes could be a potential oncogene. At the same time, the to statistical data in CA2010, there are 934 000 newly diagnosed expression and function of microRNAs were regulated by various cases of gastric cancer patients each year, and two-thirds of them factors, such as gene sequence, phosphorylation level, miRNAs are located in Eastern Europe, South America and Asia. The inci- modification enzyme and so on. Many recent studies on miRNA dence of gastric cancer in Asian countries is higher than revealed its involvement in pathogenesis of different tumors others, furthermore, Chinese account for 42% of Asian patients.1 including gastric carcinoma. The prognosis of gastric cancer depends on the stage when diagnosed, and the later stage carries poor prognosis. In general, about 50% of these patients have had metastasis at miRNAs AND TUMORIGENESIS OF GASTRIC CANCER the time of diagnosis. Subsequently, the long-term curative effect As a post-transcriptional gene regulator, miRNAs are involved in is poor. Though great progress has been made in the examination many cellular processes, including the development, differentia- and treatment, it could only improve curative effect of early tion, proliferation, apoptosis and stress reaction and so on. Human detection, but not the curative effect in case of middle and late malignant tumors including gastric cancer are usually character- stages. Current treatment still cannot significantly prolong the ized by abnormal expression of a large number of genes. Some of survival time of gastric cancer patients. them may lead to tumorgenesis as a consequence.3 MicroRNAs (miRNAs) are endogenous non-coding small miR-106-25b family including miR-25, miR-106 and miR-93b molecule RNAs, a subset of 19–24 ribonucleotide in length. shows higher expression in primary tumors of stomach and in miRNA was firstly discovered in nematode Caenorhabditis elegans, all of gastric cancer cell lines, which may take part in the process and then a variety of such molecules were found in plants of the occurrence of gastric cancer.4 In a study on 365 cases of and animals. In living cells, the miRNA molecules are modified gastric cancer, 15 miRNAs and 24 families of miRNAs were isolated by Drosha and Dicer enzyme to induce degradation or silence by application of 133 labeled-single nucleotide polymorphisms. of target mRNAs after transcription, thus inhibiting protein The results suggest that miR-25, miR-29, miR-93 and miR-106-b synthesis.2 may have an important role in the genetic susceptibility and the It is predicted that about 30% of the mRNAs in the human body molecular mechanisms of gastric cancer.5 miR-181-c is critical to are the miRNA targets, and each miRNA can regulate hundreds of the occurrence of gastric cancer through regulating oncogenes genes. They have a role on the organ development, differentiation NOTCH4 and KRAS.6 When exposed to N-nitrose compound and function, as well as tumor formation, progression, invasion (MNNG (N-methyl-N-nitro-N'-nitrosoguanidine)) in vivo or in vitro, and metastasis. Studies on function of miRNA proved that it could miR-21 is activated during the process of malignant transforma- be an oncogene or a tumor suppressor gene. The role of miRNA tion and tumorigenesis, which could induce gastric tumor. After depends on its target genes. MicroRNA targeting oncogenes could activation, miR-21 expression level is time- and dose-dependent 1Department of Thoracic Surgery & Tumor Research Institute, Tianjin Union Medicine Centre, Tianjin, China; 2Department of Microbiology & Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing, China; 3Department of Cardiothoracic Surgery, Zagazig University Hospital, Faculty of Medicine, Zagazig University, Sharkia, Egypt; 4Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, China and 5Office of Clinical Drug Trial Institution, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi, China. Correspondence: Dr. H Liu, Office of Clinical Drug Trial Institution, The Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi 830011, China. E-mail: [email protected] Received 8 January 2015; revised 15 March 2015; accepted 16 March 2015; published online 22 May 2015 Role of MicroRNAs in gastric cancer C Jiang et al 292 and it may have a role in chemical tumorigenesis through the miR-223 acts as a proto-oncogene through post-transcription regulation of death receptor Fas ligand and BTG2 (B-cell trans- regulation of its target gene FBXW7/hCdc4 (a cancer suppressor location gene 2).7 Genetic variations of miR-25, miR-29, miR-93 gene regulating apoptosis, proliferation and invasion of gastric and miR-106-b may induce increased genetic susceptibility of cancer cells).21 miR-301a can directly suppress RUNX3 (Runt- gastric cancer, and participate in the molecular mechanisms of related transcription factor 3) expression and accordingly advance gastric tumorigenesis.5 cell growth, migration and invasion.22 miR-363, via raising the Disturbance of pro-oxidant–antioxidant balance can enhance expression of MBP-1 (c-Myc promoter binding protein 1) in gastric the oxidative damage to gastric tissues and then promote the cancer SC-M1 cells, causes cell growth, progression, epithelial– occurrence of cancer. Reactive oxygen species induced by raising mesenchymal transformation and tumor formation. Endogenous miR-21 expression level in gastric cells, which cut the expression of miR-363 knockout in SC-M1 cells, by downregulating MBP-1, PDCD4 (programmed cell death protein 4), may eventually bring inhibits tumorigenesis and progression.23 about tumorigenesis.8 Both the overexpression of miR-21 and low The reduced level of miR-365 in human gastric cancer tissue expression of PDCD4 are significantly related to the degree of related to poorly differentiated tumor tissues, infiltration depth gastric cancer differentiation, clinical stage, as well as local and and progress stages, and also to the deficiency of PTEN, distant lymph node metastasis. phosphorylated Akt, p53, cyclin D1 and cdc25A. The PTEN–Akt– The gene polymorphism of G/A in miR-27a suppresses the p53–miR-365–cyclin D1/cdc25A axis serves as a new mechanism expression of mature miR-27a, which could reduce the genetic underlying gastric tumorigenesis.24 miR-372 produces its tumor- susceptibility to gastric cancer.9 In addition, in eight kinds of promoting effect by downregulating the tumor suppressor gene gastric cancer cell lines and human gastric cancer tissues, the LATS2 (large tumor suppressor 2), which can regulate gastric obviously downregulated miR-212 suppresses its target gene cancer cell cycle and apoptosis, and thus contributes to gastric MeCP2 (methyl-CpG-binding protein) expression which is asso- oncogenesis.25 ciated with occurrence of gastric cancer.10 miR-544 is another cancerogenic miRNA which can promote gastric cancer cell proliferation and cell cycle progression in vitro. Tumor-promoting effects of miRNAs Overexpression of miR-544 can inactivate the tumor suppressor gene IRX1 (iroquois homeobox 1) and diminish its expression level The aberrant expressions of miR-17-5p, miR-20a, miR-21, miR-92, in gastric cancer.26 After combining with the 3ʹ untranslated miR-106-a and miR-155 are associated with tumorigenicity, and region of GC-associated CLDN18 (claudin-18 gene) mRNA, the their elevated levels can be detected in many types of cancers. expression of miR-1303 is reduced, which will accordingly ’ In addition, inhibition of miR-27a s expression can depress the promote the occurrence and migration of gastric cancer. In growth of gastric adenocarcinoma, which proved that it could be 11 parallel, suppressed miR-1303 can inhibit proliferation, migration a gastric oncogene. and invasion of gastric cancer cells.27 Some miRNAs can promote the development of gastric cancer The gastric tumorigenesis promoting effect for miRNAs may through direct or indirect regulation of oncogenes or tumor be associated with gene polymorphism. One study on single suppressor genes. Increased expressions of miR-17, miR-18a/b, nucleotide polymorphisms of miR-196a-2 shows that the variant miR-19a, miR-20a/b, miR-21, miR-106-a/b, miR-340, miR-421 and homozygote CC can markedly increase the risk of gastric cancer, miR-658 in gastric cancer are related to downregulated levels which clearly indicates that miR-196a-2 gene mutation may of tumor suppressor genes Rb and PTEN (phosphatase and play an important role in the occurrence and progression of tensin homolog).
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