Genome-wide prioritization of disease genes and identification of disease-disease associations from an integrated human functional linkage network

Background

Recent studies have shown that the regulatory effect of microRNAs can be investigated by examining expression changes of their target genes. Given this, it is useful to define an overall metric of regulatory effect for a specific microRNA and see how this changes across different conditions.

Results

Here, we define a regulatory effect score (RE-score) to measure the inhibitory effect of a microRNA in a sample, essentially the average difference in expression of its targets versus non-targets. Then we compare the RE-scores of various microRNAs between two breast cancer subtypes: estrogen receptor positive (ER⁺) and negative (ER^-). We applied this approach to five microarray breast cancer datasets and found that the expression of target genes of most microRNAs was more repressed in ER^- than ER⁺; that is, microRNAs appear to have higher RE-scores in ER^- breast cancer. These results are robust to the microRNA target prediction method. To interpret these findings, we analyzed the level of microRNA expression in previous studies and found that higher microRNA expression was not always accompanied by higher inhibitory effects. However, several key microRNA processing genes, especially Ago2 and Dicer, were differentially expressed between ER^- and ER⁺ breast cancer, which may explain the different regulatory effects of microRNAs in these two breast cancer subtypes.

Conclusions

The RE-score is a promising indicator to measure microRNAs' inhibitory effects. Most microRNAs exhibit higher RE-scores in ER^- than in ER⁺ samples, suggesting that they have stronger inhibitory effects in ER^- breast cancers.     

Emerging roles of non‐coding RNAs in scoliosis

Scoliosis, a complex three‐dimensional deformity of the spine with the Cobb angle (a measure of the spinal lateral curvature) >10 degree, encompasses a spectrum of pathologies, including congenital, idiopathic, syndromic and neuromuscular aetiologies. The pathogenesis is multifactorial involving both environmental and genetic factors but the exact cellular and molecular mechanisms of disease development remain largely unknown. Emerging evidence showed that non‐coding RNAs (ncRNAs), namely microRNAs, long ncRNAs and circular RNAs, are deregulated in many orthopaedic diseases, including scoliosis. Importantly, these deregulated ncRNAs functionally participate in the initiation and progression of scoliosis. Here, we review recent progress in ncRNA research on scoliosis.     

miRNA-182 and the regulation of the glioblastoma phenotype - toward miRNA-based precision therapeutics

Glioblastoma (GBM) is an incurable cancer, with survival rates of just 14-16 months after diagnosis.¹ Functional genomics have identified numerous genetic events involved in GBM development. One of these, the deregulation of microRNAs (miRNAs), has been attracting increasing attention due to the multiple biologic processes that individual miRNAs influence. Our group has been studying the role of miR-182 in GBM progression, therapy resistance, and its potential as GBM therapeutic. Oncogenomic analyses revealed that miR-182 is the only miRNA, out of 470 miRNAs profiled by The Cancer Genome Atlas (TCGA) program, which is associated with favorable patient prognosis, neuro-developmental context, temozolomide (TMZ) susceptibility, and most significantly expressed in the least aggressive oligoneural subclass of GBM. miR-182 sensitized glioma cells to TMZ-induced apoptosis, promoted glioma initiating cell (GIC) differentiation, and reduced tumor cell proliferation via knockdown of Bcl2L12, c-Met and HIF2A.² To deliver miR-182 to intracranial gliomas, we have characterized Spherical Nucleic Acids covalently functionalized with miR-182 sequences (182-SNAs). Upon systemic administration, 182-SNAs crossed the blood-brain/blood-tumor barrier (BBB/BTB), reduced tumor burden, and increased animal subject survival.^2-4 Thus, miR-182-based SNAs represent a tool for systemic delivery of miRNAs and a novel approach for the precision treatment of malignant brain cancers.     

A microRNA component of the hypoxic response

microRNAs participate in a wide variety of physiological and pathological cellular processes. Recent studies have established a link between a specific group of microRNAs and hypoxia, a key feature of the neoplastic microenvironment. A significant proportion of the hypoxia-regulated microRNAs (HRMs) are also overexpressed in human cancers, suggesting a role in tumorigenesis. Preliminary evidence suggests that they could affect important processes such as apoptosis, proliferation and angiogenesis. Several HRMs exhibit induction in response to HIF activation, thus extending its repertoire of targets beyond translated genes. In the present review, we discuss the emerging roles of HRMs in oxygen deprivation in cancer context.     

Recent advances in the identification of the host factors involved in dengue virus replication

Dengue virus (DENV) belongs to the genus Flavivirus of the family Flaviviridae and it is primarily transmitted via Aedes aegypti and Aedes albopictus mosquitoes. The life cycle of DENV includes attachment, endocytosis, protein translation, RNA synthesis, assembly, egress, and maturation. Recent researches have indicated that a variety of host factors, including cellular proteins and microRNAs, positively or negatively regulate the DENV replication process. This review summarizes the latest findings (from 2014 to 2016) in the identification of the host factors involved in the DENV life cycle and Dengue infection.

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miRACA: A database for miRNAs associated with cancers and age related disorders (ARD)

Background

With the given diversity and abundance of several targets of miRNAs, they functionally appear to interact with several elements of the multiple cellular networks to maintain physiologic homeostasis. They can function as tumor suppressors or oncogenes, whose under or overexpression has both diagnostic and prognostic significance in various cancers while being implicated as prospective regulators of age-related disorders (ARD) as well. Establishing a concatenate between ARD and cancers by looking into the insights of the shared miRNAs may have a practical relevance.

Methods

In the present work, we performed network analysis of miRNA-disease association and miRNA-target gene interaction to prioritize miRNAs that play significant roles in the manifestation of cancer as well as ARD. Also, we developed a repository that stores miRNAs common to both ARD and cancers along with their target genes.

Results

We have comprehensively curated all miRNAs that we found to be shared in both the diseases in the human genome and established a database, miRACA (Database for microRNAs Associated with Cancers and ARD) that currently houses information of 1648 miRNAs that are significantly associated with 38 variants supported with pertinent data. It has been made available online at http://genomeinformatics.dtu.ac.in/miraca/ for easy retrieval and utilization of data by the scientific community.

Conclusion

To the best of our knowledge, our database is the first attempt at compilation of such data. We believe this work may serve as a significant resource and facilitate the analysis of miRNA regulatory mechanisms shared between cancers and ARD to apprehend disease etiology.

     

Prognostic value of the tumor-specific ceRNA network in epithelial ovarian cancer

Epithelial ovarian cancer is one of the leading causes of cancer-related death worldwide. Growing evidence indicates that multiple complex altered pathways play important regulatory roles in the development and progression of a variety of cancers, including epithelial ovarian cancer. However, the underlying mechanisms remain unclear. First, we identified differentially expressed messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and microRNAs (miRNAs) in epithelial ovarian cancer by comparing the expression profiles between epithelial ovarian cancer samples and normal tissue samples in different GEO datasets. Then, GO- and KEGG-pathway-enrichment analyses were applied to investigate the primary functions of the overlapped differentially expressed mRNAs. Moreover, the primary enriched genes were used to construct the signal-network with Cytoscape software. In addition, we integrated the relationship among lncRNAs-miRNAs-mRNAs to create a competing endogenous RNA network. Finally, mRNAs that were associated with patient prognosis in epithelial ovarian cancer were selected using univariate Cox regression analysis. A total of 2,225 mRNAs, 336 lncRNAs, and 14 miRNAs were shown to be differentially expressed in epithelial ovarian cancer compared with normal tissues. The dysregulated mRNAs were primarily enriched in cell division and signal transduction, according to Gene Ontology, whereas, according to KEGG, they were primarily enriched in metabolic pathways and pathways in cancer. A total of 10 mRNAs were associated with patient prognosis in ovarian cancer. This study identifies a novel lncRNA–miRNA–mRNA network, which may suggest potential molecular mechanisms underlying the development of epithelial ovarian cancer, providing new insights for survival prediction and interventional strategies for epithelial ovarian cancer.     

Identification of novel caspase/autophagy‐related gene switch to cell fate decisions in breast cancers

Objectives

Caspases, a family of cysteine proteases with unique substrate specificities, contribute to apoptosis, whereas autophagy‐related genes (ATGs) regulate cytoprotective autophagy or autophagic cell death in cancer. Accumulating evidence has recently revealed underlying mechanisms of apoptosis and autophagy; however, their intricate relationships still remain to be clarified. Identification of caspase/ATG switches between apoptosis and autophagy may address this problem.

Materials and methods

Identification of caspase/ATG switches was carried out using a series of elegant systems biology & bioinformatics approaches, such as network construction, hub protein identification, microarray analyses, targeted microRNA prediction and molecular docking.

Results

We computationally constructed the global human network from several online databases and further modified it into the basic caspase/ATG network. On the basis of apoptotic or autophagic gene differential expressions, we identified three molecular switches [including androgen receptor, serine/threonine‐protein kinase PAK‐1 (PAK‐1) and mitogen‐activated protein kinase‐3 (MAPK‐3)] between certain caspases and ATGs in human breast carcinoma MCF‐7 cells. Subsequently, we identified microRNAs (miRNAs) able to target androgen receptor, PAK‐1 and MAPK‐3, respectively. Ultimately, we screened a range of small molecule compounds from DrugBank, able to target the three above‐mentioned molecular switches in breast cancer cells.

Conclusions

We have systematically identified novel caspase/ATG switches involved in miRNA regulation, and predicted targeted anti‐cancer drugs. These findings may uncover intricate relationships between apoptosis and autophagy and thus provide further new clues towards possible cancer drug discovery.

     

Small nucleolar RNAs in cancer

Non-coding RNAs (ncRNAs) are important regulatory molecules involved in various physiological and cellular processes. Alterations of ncRNAs, particularly microRNAs, play crucial roles in tumorigenesis. Accumulating evidence indicates that small nucleolar RNAs (snoRNAs), another large class of small ncRNAs, are gaining prominence and more actively involved in carcinogenesis than previously thought. Some snoRNAs exhibit differential expression patterns in a variety of human cancers and demonstrate capability to affect cell transformation, tumorigenesis, and metastasis. We are beginning to comprehend the functional repercussions of snoRNAs in the development and progression of malignancy. In this review, we will describe current studies that have shed new light on the functions of snoRNAs in carcinogenesis and the potential applications for cancer diagnosis and therapy.     

MicroRNA-mediated regulation of <Emphasis Type="Italic">KRAS</Emphasis> in cancer

While microRNAs (miRNAs) and the KRAS oncogene are known to be dysregulated in various cancers, little is known about the role of miRNAs in the regulation of KRAS in cancer. Here we review a selection of studies published in 2014 that have contributed to our understanding of the molecular mechanisms of KRAS regulation by miRNAs and the clinical relevance of sequence variants that may interfere with functional miRNA-mediated KRAS regulation.