Early studies have shown how aberrantly expressed microRNAs are a hallmark of several diseases like cancer. MicroRNA expression profiling was shown to be associated with tumour development, progression and response to therapy, suggesting their possible use as diagnostic, prognostic and predictive biomarkers. Moreover, based on the increasing number of studies demonstrating that microRNAs can function as potential oncogenes or oncosuppressor genes, with the goal to improve disease response and increase cure rates, miRNA-based anticancer therapies have recently been exploited, either alone or in combination with current targeted therapies. The advantage of using microRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. Here, we review our current knowledge about the involvement of microRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools.

https://www.embopress.org/doi/pdf/10.1002/emmm.201100209

MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review

MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

As much as the cellular viability is important for the living organisms, the elimination of unnecessary or damaged cells has the opposite necessity for the maintenance of homeostasis in tissues, organs and the whole organism. Apoptosis, a type of cell death mechanism, is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body. Apoptosis can be triggered by intrinsically or extrinsically through death signals from the outside of the cell. Any abnormality in apoptosis process can cause various types of diseases from cancer to auto-immune diseases. Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family of genes, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis. In this review, we discuss the basic features of apoptosis and have focused on the gene families playing critical roles, activation/inactivation mechanisms, upstream/downstream effectors, and signaling pathways in apoptosis on the basis of cancer studies. In addition, novel apoptotic players such as miRNAs and sphingolipid family members in various kind of cancer are discussed.

/pdf/major-apoptotic-mechanisms-and-genes-involved-in-apoptosis-u8kyxhyji8.pdf

Major apoptotic mechanisms and genes involved in apoptosis.

Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

/pdf/the-bcl-2-protein-family-bh3-mimetics-and-cancer-therapy-14cqgx7nqg.pdf

The BCL-2 protein family, BH3-mimetics and cancer therapy.

The identification of disease-related microRNAs is vital for understanding the pathogenesis of diseases at the molecular level, and is critical for designing specific molecular tools for diagnosis, treatment and prevention. Experimental identification of disease-related microRNAs poses considerable difficulties. Computational analysis of microRNA-disease associations is an important complementary means for prioritizing microRNAs for further experimental examination. Herein, we devised a computational model to infer potential microRNA-disease associations by prioritizing the entire human microRNAome for diseases of interest. We tested the model on 270 known experimentally verified microRNA-disease associations and achieved an area under the ROC curve of 75.80%. Moreover, we demonstrated that the model is applicable to diseases with which no known microRNAs are associated. The microRNAome-wide prioritization of microRNAs for 1,599 disease phenotypes is publicly released to facilitate future identification of disease-related microRNAs. We presented a network-based approach that can infer potential microRNA-disease associations and drive testable hypotheses for the experimental efforts to identify the roles of microRNAs in human diseases.

/pdf/prioritization-of-disease-micrornas-through-a-human-phenome-55u4ygi4iu.pdf

Prioritization of disease microRNAs through a human phenome-microRNAome network

MicroRNA-153 (miR-153) is a brain-specific miRNA that is expressed at a significantly lower level in glioblastoma (GBM) relative to non-neoplastic brain tissue. Although the expression pattern of miR-153 has been extensively established, its target genes and cellular mechanism remain undefined. To investigate into the potential function of miR-153 in glioblastmas, we transfected a GBM cell line DBTRG-05MG with synthetic miR-153 oligos and observed decreased cell proliferation and increased apoptosis. Bioinformatics analysis revealed that anti-apoptosis family member B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1) are potential targets of miR-153. Indeed, Western blot analysis indicated that miR-153 downregulated both Bcl-2 and Mcl-1 at the protein levels. Single strand miR-153 inhibitor, which forms complementary base-pair with endogenous miR-153, efficiently blocked the apoptosis and target protein degradation induced by overexpression of miR-153. By luciferase reporter assays, we further showed that miR-153 inhibited Bcl-2 and Mcl-1 expressions by directly targeting the 3'UTR regions of their respective mRNAs.

Downregulations of B-cell lymphoma 2 and myeloid cell leukemia sequence 1 by microRNA 153 induce apoptosis in a glioblastoma cell line DBTRG-05MG.

MicroRNAs (miRNAs) are one class of short, endogenous RNAs which can regulate gene expression at the post-transcriptional level. Previous analysis revealed that mammalian miRNAs tend to cluster on chromosomes. However, the functional consequences of this clustering and conservation property are largely unknown. In this study we present a method to identify signaling pathways targeted by clustered miRNAs. We performed a computational screen for mouse signaling pathways targeted by miRNA clusters. Here, we report that the target genes of 3 miRNA clusters are overrepresented in 15 signaling pathways. We provided experimental evidence that one miRNA cluster, mmu-mir-183–96–182 targets Irs1, Rasa1, and Grb2, all of which are located in the insulin signaling pathway. Theses results suggest that by targeting components with different roles along a signaling pathway, different members of one miRNA cluster can act as a whole to coordinately control the signal transduction process.

/pdf/a-computational-screen-for-mouse-signaling-pathways-targeted-3xa5un5s85.pdf

A computational screen for mouse signaling pathways targeted by microRNA clusters.

MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression by inhibiting translation or by promoting mRNA degradation. Previously, we established that microRNA-153 (miR-153) induces apoptosis by downregulating B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1) protein expression levels in glioblastoma cell line DBTRG-05MG. In our study, we show that ectopic expression of miR-153 also inhibits the protein kinase B (PKB/Akt) pathway via reducing the protein level of insulin receptor substrate-2 (Irs-2). Moreover, simultaneous treatment with the chromatin-modifying drugs 4-phenylbutyric acid and 5-aza-2′-deoxycytidine induces miR-153 expression to suppress Irs-2, Bcl-2 and Mcl-1 expressions, thus downregulating the survival but upregulating the apoptotic pathways, implying that tumor suppressor miR-153 is a dual life and death regulator.

Chromatin-modifying drugs induce miRNA-153 expression to suppress Irs-2 in glioblastoma cell lines.

Hunting for robust gene signature from cancer profiling data: sources of variability, different interpretations, and recent methodological developments.

MicroRNAs (miRNAs) are a class of ∼22-nucleotide endogenous noncoding RNAs which regulate target gene expression via repressing translation or promoting mRNAs degradation. Any individual mammalian miRNA often has more than a hundred predicted mRNA targets and that close to one thirds of all mRNA transcripts bear one or more conserved miRNA binding sites in their 3'-untranslated region. Enrichment analysis of miRNA targets has become a standard technique to elucidating hierarchical functions of miRNAs in gene regulatory networks. In this protocol, we discuss analytical methods and use of computational tools in a step-by-step manner. Important details are also provided to help researchers choose more appropriate tools for a given type of analysis. Available Web-based resources for enrichment analysis of miRNA targets are summarized.

Chi-Wai Wong

Papers

Downregulations of B-cell lymphoma 2 and myeloid cell leukemia sequence 1 by microRNA 153 induce apoptosis in a glioblastoma cell line DBTRG-05MG.

A computational screen for mouse signaling pathways targeted by microRNA clusters.

Chromatin-modifying drugs induce miRNA-153 expression to suppress Irs-2 in glioblastoma cell lines.

Hunting for robust gene signature from cancer profiling data: sources of variability, different interpretations, and recent methodological developments.

Enrichment analysis of miRNA targets.