Circular RNAs (circRNAs) are a class of single-stranded, covalently closed RNA molecules with a variety of biological functions. Studies have shown that circRNAs are involved in a variety of biological processes and play an important role in the development of various complex diseases, so the identification of circRNA-disease associations would contribute to the diagnosis and treatment of diseases. In this review, we summarize the discovery, classifications and functions of circRNAs and introduce four important diseases associated with circRNAs. Then, we list some significant and publicly accessible databases containing comprehensive annotation resources of circRNAs and experimentally validated circRNA-disease associations. Next, we introduce some state-of-the-art computational models for predicting novel circRNA-disease associations and divide them into two categories, namely network algorithm-based and machine learning-based models. Subsequently, several evaluation methods of prediction performance of these computational models are summarized. Finally, we analyze the advantages and disadvantages of different types of computational models and provide some suggestions to promote the development of circRNA-disease association identification from the perspective of the construction of new computational models and the accumulation of circRNA-related data.

MicroRNAs and complex diseases: from experimental results to computational models.

MicroRNAs (miRs, miRNAs) are small molecules of 18–22 nucleotides that serve as important regulators of gene expression at the post-transcriptional level. One of the mechanisms through which miRNAs regulate gene expression involves the interaction of their “seed” sequences primarily with 3′-end and more rarely with 5′-end, of mRNA transcribed from target genes. Numerous studies over the past decade have been devoted to quantitative and qualitative assessment of miRNAs expression and have shown remarkable changes in miRNA expression profiles in various diseases. Thus, profiling of miRNA expression can be an important tool for diagnostics and treatment of disease. However, less attention has been paid towards understanding the underlying reasons for changes in miRNA expression, especially in cancer cells. The purpose of this review is to analyze and systematize current data that explains reasons for changes in the expression of miRNAs. The review will cover both transcriptional (changes in gene expression and promoter hypermethylation) and post-transcriptional (changes in miRNA processing) mechanisms of regulation of miRNA expression, as well as effects of endogenous (hormones, cytokines) and exogenous (xenobiotics) compounds on the miRNA expression. The review will summarize the complex multilevel regulation of miRNA expression, in relation to cell type, physiological state of the body and various external factors.

/pdf/regulatory-mechanisms-of-microrna-expression-g8cad92fdw.pdf

Regulatory mechanisms of microRNA expression

The major function of Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is to regulate cell metabolism. However, emerging evidence indicates that IGF2BP2 plays a role in cancer, but the underlying mechanism is largely unknown. Here we showed that upregulation of IGF2BP2 is associated with poor outcomes of pancreatic cancer patients and suppression of IGF2BP2 inhibits cell proliferation. We further showed that IGF2BP2 regulates lncRNA DANCR. Ectopic expression IGF2BP2 enhances, whereas knockdown (KD) or knockout (KO) of IGF2BP2 suppresses DANCR expression. Moreover, in vivo RNA precipitation and reciprocal RNA immunoprecipitation revealed that IGF2BP2 interacts with DANCR. DANCR promotes cell proliferation and stemness-like properties. Experiments with xenograft models revealed that while ectopic expression of DANCR promotes, DANCR KO suppresses tumor growth. Mechanistically, DANCR is modified at N6-methyladenosine (m6A) and mutagenesis assay identified that adenosine at 664 of DANCR is critical to the interaction between IGF2BP2 and DANCR where IGF2BP2 serves a reader for m6A modified DANCR and stabilizes DANCR RNA. Together, these results suggest that DANCR is a novel target for IGF2BP2 through m6A modification, and IGF2BP2 and DANCR work together to promote cancer stemness-like properties and pancreatic cancer pathogenesis.

/pdf/igf2bp2-regulates-dancr-by-serving-as-an-n6-methyladenosine-313sbid165.pdf

IGF2BP2 regulates DANCR by serving as an N6-methyladenosine reader

RNA-binding protein (RBP) has a highly dynamic spatiotemporal regulation process and important biological functions. They are critical to maintain the transcriptome through post-transcriptionally controlling the processing and transportation of RNA, including regulating RNA splicing, polyadenylation, mRNA stability, mRNA localization, and translation. Alteration of each process will affect the RNA life cycle, produce abnormal protein phenotypes, and thus lead to the occurrence and development of tumors. Here, we summarize RBPs involved in tumor progression and the underlying molecular mechanisms whereby they are regulated and exert their effects. This analysis is an important step towards the comprehensive characterization of post-transcriptional gene regulation involved in tumor progression.

/pdf/rna-binding-proteins-in-tumor-progression-17fgfh4jy8.pdf

RNA-binding proteins in tumor progression

N6-Methyladenosine (m6A) modification has been implicated in multiple processes for colon cancer development. IGF2BP3 was a newly reported m6A reader, whereas its role in colon cancer remains unclear. The expression of m6A associated enzymes and total m6A level were measured by Western Blotting analysis and m6A RNA Methylation Quantification Kit respectively. Cell cycle was analyzed by flowcytometry. The interaction of IGF2BP3 and related targets was analyzed by RNA immunoprecipitation (RIP) and m6A RNA immunoprecipitation (MeRIP) assays. We investigated all m6A regulated enzymes in colon cancer and found only the overexpression of IGF2BP3 was associated with cancer progression and survival based on The Cancer Genome Atlas (TCGA) databases. Additionally, we also demonstrated IGF2BP3 was associated with DNA replication in the cell cycle. Knockdown of IGF2BP3 significantly repressed percentage of S phase of cell cycle as well as cell proliferation. Further research demonstrated IGF2BP3 bound to the mRNA of Cyclin D1 (CCND1, checkpoint of G1/S phase of cell cycle) and reduced its mRNA stability via reading m6A modification in the CDS region. Overexpression of Cyclin D1 in IGF2BP3 down-regulated cells completely rescued the inhibited percentage of S phase in cell cycle as well as cell proliferation. Additionally, we also demonstrated a similar role of IGF2BP3 at VEGF. IGF2BP3 bound to the mRNA of VEGF and reads m6A modification, thus regulated both expression and stability of VEGF mRNA. Knockdown of IGF2BP3 repressed angiogenesis in colon cancer via regulating VEGF. Knockdown of IGF2BP3 repressed DNA replication in the S phase of cell cycle and angiogenesis via reading m6A modification of CCND1 and VEGF respectively. IGF2BP3 was a possible prognosis marker and potential therapeutic target of colon cancer.

/pdf/rna-n6-methyladenosine-reader-igf2bp3-regulates-cell-cycle-3jj57ibtty.pdf

RNA N6-Methyladenosine Reader IGF2BP3 Regulates Cell Cycle and Angiogenesis in Colon Cancer

IGF2BP2 promotes colorectal cancer cell proliferation and survival through interfering with RAF-1 degradation by miR-195.

Altered expressions of microRNAs (miRNAs) are reported in pancreatic cancer and associate with cancer pathogenesis, apoptosis, and cell growth, thereby functioning as either tumor suppressors or oncogenes. However, the majority of studies focus on defining the regulatory functions of miRNAs, whereas few investigations are directed toward assessing how the miRNA themselves are transcriptionally regulated. In this study, integration of published multi-level expression data and bioinformatics computational approach was used to predict two regulation mechanisms: transcription factors (TF)-miRNA-mRNA regulation and long non-coding RNA(lncRNA)-miRNA-mRNA regulation. To identify differentially expressed mRNAs, miRNAs, and lncRNAs, we integrated microarray expression data in pancreatic cancer tissues and normal tissues. Combination of differentially expressed mRNAs and miRNAs with miRNA-mRNA interactions based on crosslinking and immunoprecipitation followed by high-throughput sequencing (CLIP-Seq) data from StarBas, we constructed miRNA-mRNA regulatory network. Then we constructed two regulatory networks including TF-miRNA-mRNA and lncRNA-miRNA-mRNA based on chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) data from ChIPBase and CLIP-Seq data. A total of 4385 mRNAs, 500 miRNAs, and 21 lncRNAs were differentially expressed, of which, 18 mRNAs and 54 miRNAs are with high confidence. In miRNA-mRNA regulatory network, interrelated miRNAs target 1701 differentially regulated mRNAs. By constructing regulatory network, 19miRNAs including hsa-miR-137, hsa-miR-206, hsa-miR-429, hsa-miR-320d, and hsa-miR-320c are predicted to participate in lncRNA-miRNA-mRNA regulation. Furthermore, 8 miRNAs including hsa-mir-137, hsa-mir-206, hsa-mir-429, hsa-mir-375, hsa-mir-326, hsa-mir-217, hsa-mir-301b, and hsa-mir-184 are predicted to participate in TF-miRNA-mRNA regulation. In an integrated data analysis, we reveal large-scale effects of interrelated miRNAs and provide a model for predicting the mechanism of miRNAs disorder. Our study provides a new insight into understanding the transcriptional regulation of pancreatic cancer.

Bioinformatics Method to Predict Two Regulation Mechanism: TF–miRNA–mRNA and lncRNA–miRNA–mRNA in Pancreatic Cancer

Next-generation sequencing technology allows simultaneous analysis of multiple susceptibility genes for clinical cancer genetics. In this study, multiplex genetic testing was conducted in a Chinese family with multiple cases of cancer to determine the variations in cancer predisposition genes. The family comprises a mother and her five daughters, of whom the mother and the eldest daughter have cancer and the secondary daughter died of cancer. We conducted multiplex genetic testing of 90 cancer susceptibility genes using the peripheral blood DNA of the mother and all five daughters. WRN frameshift mutation is considered a potential pathogenic variation according to the guidelines of the American College of Medical Genetics. A novel WRN frameshift mutation (p.N1370Tfs*23) was identified in the three cancer patients and in the youngest unaffected daughter. Other rare non-synonymous germline mutations were also detected in DICER and ELAC2. Functional mutations in WRN cause Werner syndrome, a human autosomal recessive disease characterized by premature aging and associated with genetic instability and increased cancer risk. Our results suggest that the WRN frameshift mutation is important in the surveillance of other members of this family, especially the youngest daughter, but the pathogenicity of the novel WRN frameshift mutation needs to be investigated further. Given its extensive use in clinical genetic screening, multiplex genetic testing is a promising tool in clinical cancer surveillance.

/pdf/a-novel-wrn-frameshift-mutation-identified-by-multiplex-sc9tmp9c9c.pdf

A Novel WRN Frameshift Mutation Identified by Multiplex Genetic Testing in a Family with Multiple Cases of Cancer

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IGF2BP2 promotes colorectal cancer cell proliferation and survival through interfering with RAF-1 degradation by miR-195.

Bioinformatics Method to Predict Two Regulation Mechanism: TF–miRNA–mRNA and lncRNA–miRNA–mRNA in Pancreatic Cancer

A Novel WRN Frameshift Mutation Identified by Multiplex Genetic Testing in a Family with Multiple Cases of Cancer