miRNAs in human cancer

Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. miRNA targeting is mostly achieved through specific base-pairing interactions between the 5' end ('seed' region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3' UTR lead to more effective mRNA destabilization. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. To provide a critical overview of miRNA dysregulation in cancer, we first discuss the methods currently available for studying the role of miRNAs in cancer and then review miRNA genomic organization, biogenesis and mechanism of target recognition, examining how these processes are altered in tumorigenesis. Given the critical role miRNAs play in tumorigenesis processes and their disease-specific expression, they hold potential as therapeutic targets and novel biomarkers.     

构建编码基因-非编码RNA调控网络挖掘前列腺癌潜在致病因子

目的 基于前列腺癌的编码基因-非编码RNA调控网络识别潜在的生物标记物.方法 利用前列腺癌的lncRNA、miRNA和mRNA表达谱数据及它们与转录因子之间的靶向关系,构建编码基因-非编码RNA三维调控网络,挖掘ceRNA子网,识别潜在竞争性的lncRNA并筛选前列腺癌潜在的致病因子.结果 从ceRNA子网中识别出4个lncRNA竞争性的结合了5个miRNA间接调控了63个基因的表达,功能预测这些lncRNA参与了激素调节;基于网络拓扑属性,挖掘出一个包含了16个lncRNAs、2个miRNAs、4个mRNAs的生物标记物.结论 多种调控因子如TF、lncRNA、miRNA、mRNA共同作用影响前列腺癌的发生发展,其中有些lncRNA作为ceRNA来发挥基因表达调控的作用.     

MicroRNA–mRNA interactions in colorectal cancer and their role in tumor progression

MicroRNAs (miRNA/miR) play an important role in gene regulatory networks through targeting mRNAs. They are involved in diverse biological processes such as cell proliferation, differentiation, angiogenesis, and apoptosis. Due to their pivotal effects on multiple genes and pathways, dysregulated miRNAs have been reported to be associated with different diseases, including colorectal cancer (CRC). Recent evidence indicates that aberrant miRNA expression is tightly linked with the initiation and progression of CRC. To elucidate the influence of miRNA regulation in CRC, it is critical to identify dysregulated miRNAs, their target mRNA genes and their involvement in gene regulatory and signaling networks. Various experimental and computational studies have been conducted to decipher the function of miRNAs involved in CRC. Experimental studies that are used for this purpose can be classified into two categories: direct/individual and indirect/high‐throughput gene expression studies. Here we review miRNA target identification studies related to CRC with an emphasis on experimental data based on Luciferase reporter assays. Recent advances in determining the function of miRNAs and the signaling pathways they are involved in have also been summarized. The review helps bioinformaticians and biologists to find extensive information about downstream targets of dysregulated miRNAs, and their pro‐/anti‐CRC effects. © 2015 Wiley Periodicals, Inc.     

Genetic and epigenetic alterations of microRNAs and implications for human cancers and other diseases

MicroRNAs (miRNAs) are a well‐studied group of noncoding RNAs that control gene expression by interacting mainly with messenger RNA. It is known that miRNAs and their biogenesis regulatory machineries have crucial roles in multiple cell processes; thus, alterations in these genes often lead to disease, such as cancer. Disruption of these genes can occur through epigenetic and genetic alterations, resulting in aberrant expression of miRNAs and subsequently of their target genes. This review focuses on the disruption of miRNAs and their key regulatory machineries by genetic alterations, with emphasis on mutations and epigenetic changes in cancer and other diseases. © 2015 Wiley Periodicals, Inc.     

Comprehensive analysis of tumor immune infiltration associated with endogenous competitive RNA networks in lung adenocarcinoma

Cancer immunotherapy has achieved unprecedented success in the treatment of cancer. However, different patients have different responses to immunotherapy. More and more studies have shown that tumor immune heterogeneity has an important influence on the prognosis of cancer. Therefore, understanding the clinical impact of tumor immune infiltration and the regulatory mechanism of RNA molecules is crucial for exploring the pathogenesis of lung adenocarcinoma (LUAD) and the development of immunotherapy protocols.The endogenous competitive RNA hypothesis provides new ideas for studying immune heterogeneity. Therefore, by using the method of immune genomics, this article explores the relationship between immune infiltration and prognosis of patients with lung adenocarcinoma, and found that B-cell immune infiltration highly affects the survival of patients. Through differential analysis, differential mRNAs, lncRNAs and miRNAs were extracted, and 318 differentially expressed mRNAs related to B cell immunity were screened by correlation analysis, and prognosis of patients with COX risk regression model was predicted and analyzed. Through multiple database searches, an immune-related ceRNA regulatory network was constructed, containing 3 key mRNAs, 4 miRNAs, and 50 lncRNAs. Three mRNAs and most miRNAs, lncRNAs, are significantly associated with LUAD prognosis. Bioinformatics analysis of the network showed that LINC00337 may up-regulate the expression of PBK and KIF23 through competitive binding of has-mir-373 and has-mir-519d. The competitive binding of has-mir-373 and has-mir-372 can up-regulate the expression of SLC7A11. The interaction between these RNAs may have an important regulatory role in the immune infiltration in lung adenocarcinoma, thereby affecting the patient's prognosis and immunotherapy efficacy.     

Oncogenic Activity of miR-650 in Prostate Cancer Is Mediated by Suppression of CSR1 Expression

Cellular stress response 1 (CSR1) is a tumor suppressor gene whose expression was frequently down-regulated in prostate cancer. The mechanism of its down-regulation, however, is not clear. Here, we show that the 3′ untranslated region of CSR1 contains a target site of miR-650. High level of miR-650 was found in prostate cancer samples and cell lines. Degradation of miR-650 by specific inhibitor dramatically increased the expression levels of CSR1. Interaction between miR-650 and its target site in the 3′ untranslated region was validated through luciferase reporter system. Mutation at the target site completely abrogated the activity of miR-650 on the 3′ untranslated region of CSR1. Inhibition of miR-650 reversed the expression suppression of CSR1, suppressed colony formation, and blocked cell cycle entry to the S phase of both PC3 and DU145 cells. Animal model showed significant decrease of tumor volume, rate of metastasis, and mortality of severe combined immunodeficient mice xenografted with PC3 or DU145 cells transformed with inhibitor of miR-650. Our analyses demonstrate that suppression of CSR1 expression is a novel mechanism critical for the oncogenic activity of miR-650.miRNAs are some well-conserved small noncoding RNA molecules of 20 to 22 bases in plants and mammals, playing a critical role in epigenetic regulation of gene expression.¹ miRNAs silence targeted mRNA through base-pairing with the complementary sequences within the 3′ untranslated regions (UTRs) of mRNA molecules and block the ribosome complexes from translating the mRNAs into proteins.² Approximately 1000 miRNAs are present in the human genome and are projected to target up to 60% of mRNA species.^3,4 The differential expression of miRNA in different types of tissues may lead to differentiation of cells and tissues that form the organ system of the human body. Different sets of expressed miRNAs are found in different cell types and tissues.⁵Aberrant expression of miRNA is implicated in numerous human diseases. Abnormal expressions of a family of miRNAs targeted at DNA repairing pathways were implicated as potential causes of colon cancer and glioblastoma multiformis.^6,7 Abnormal expression of miR-650 was previously shown to be associated with melanoma,⁸ gastric cancer,⁹ non-small cell lung cancer,¹⁰ chronic lymphocytic leukemia,¹¹ and hepatocellular carcinoma.¹² High level of miR-650 was shown to be a prognosticator for lymph node involvement and more aggressive clinical outcomes of lung adenocarcinoma. However, the mechanism of miR-650–induced tumorigenesis remains unclear. Here, we showed that miR-650 was significantly up-regulated in prostate cancer (PC). High expression level of miR-650 was significantly associated with lower prostate-specific antigen–free survival rate. Expression of miR-650 inversely correlated with that of cellular stress response 1 (CSR1), a tumor suppressor gene that is frequently down-regulated in PC. The oncogenic activity of miR-650 in PC is mediated by inhibition of CSR1 expression.     

前列腺癌组织中miRNAs的表达及意义

目的研究前列腺癌组织中6种miRNAs的表达及其意义,并探讨它们在前列腺癌诊断中的应用价值。方法采用核酸分子原位杂交(in situ hybridizationI,SH)技术,结合组织微阵列平台分别检测38例良性前列腺增生(benign prostate hyperpla-sia,BPH)和52例前列腺癌(prostatic cancer,PCa)中6种miRNAs的表达情况。结果 6种miRNAs在PCa中的表达率与BPH比较差异均有统计学意义(P<0.05)。6种miRNAs的表达均与PCa的Gleason评分相关(P<0.05);与患者的年龄及血清PSA水平均无明显相关性(P>0.05)。miR-15b、miR-182和miR-96的表达与PCa的临床分期相关(P<0.05);miR-96的表达与肿瘤累及前列腺叶数相关(P<0.05)。结论 miRNAs与PCa的发生、发展以及生物学行为有关,并可能作为PCa诊断及判断预后的生物标记物。     

Identification of a novel miRNA-target gene regulatory network in osteosarcoma by integrating transcriptome analysis

Osteosarcoma remains a leading cause of cancer death in children and young adolescents. Although the introduction of multiagent chemotherapy, survival rates have not improved in two decades. Therefore, it is urgently needed to know the details regarding molecular etiology to driving therapeutic inroads for this disease. In this study we performed an integrated analysis of miRNA and mRNA expression data to explore the dysregulation of miRNA and miRNA-target gene regulatory network underlying OS. 59 differentially expressed miRNAs were identified, with 28 up-regulated and 31 down-regulated miRNAs by integrating OS miRNA expression data sets available. Using miRWalk databases prediction, we performed an anticorrelated analysis of miRNA and genes expression identified by a integrated analysis of gene expression data to identify 109 differently expressed miRNA target genes. A novel miRNA-target gene regulatory network was constructed with the miRNA-target gene pairs. miR-19b-3p, miR-20a-5p, miR-124-3p and their common target CCND2, the nodal points of regulatory network, may play important roles in OS. Bioinformatics analysis of biological functions and pathways demonstrated that target genes of miRNAs are highly correlated with carcinogenesis. Our findings may help to understand the molecular mechanisms of OS and identify targets of effective targeted therapies for OS.