No abstract

Bioinformatics tools are imperative for the in depth analysis of heterogeneous high-throughput data. Most of the software tools are developed by specific laboratories or groups or companies wherein they are designed to perform the required analysis for the group. However, such software tools may fail to capture “what the community needs in a tool”. Here, we describe a novel community-driven approach to build a comprehensive functional enrichment analysis tool. Using the existing FunRich tool as a template, we invited researchers to request additional features and/or changes. Remarkably, with the enthusiastic participation of the community, we were able to implement 90% of the requested features. FunRich enables plugin for extracellular vesicles wherein users can download and analyse data from Vesiclepedia database. By involving researchers early through community needs software development, we believe that comprehensive analysis tools can be developed in various scientific disciplines.

Tumor-derived exosomes are emerging mediators of tumorigenesis and tissue-specific metastasis. Proteomic profiling has identified Annexin A2 as one of the most highly expressed proteins in exosomes; however, studies focused on the biological role of exosomal-AnnexinA2 (exo-AnxA2) are still lacking. In this study, mechanistic insight was sought regarding exo-AnxA2 and its function in angiogenesis and breast cancer metastasis. Multiple in vitro and in vivo techniques were used to study the role of exo-AnxA2 in angiogenesis. Using atomic force microscopy (AFM) and Western blotting, exo-AnxA2 expression was characterized in normal and breast cancer cells. In addition, organ specific metastatic breast cancer cells and animal models were used to define the role exo-AnxA2 in breast cancer metastasis. Results revealed that exo-AnxA2 expression is significantly higher in malignant cells than normal and pre-metastatic breast cancer cells. In vitro and in vivo studies demonstrated that exo-AnxA2 promotes tPA-dependent angiogenesis. Furthermore, in vivo analysis indicated that metastatic exosomes create a favorable microenvironment for metastasis and exo-AnxA2 plays an important role in this process, since priming with AnxA2-depleted exosomes reduces brain (~4-fold) and lung (~2-fold) metastasis. Upon delineating the mechanism it was discovered that exo-AnxA2 causes macrophage-mediated activation of the p38MAPK, NF-κB, and STAT3 pathways and increased secretion of IL-6 and TNF-alpha. These data demonstrate an important role for exo-AnxA2 in breast cancer pathogenesis.

The recognition of functional roles for transcribed long non-coding RNA (lncRNA) has provided a new dimension to our understanding of cellular physiology and disease pathogenesis. LncRNAs are a large group of structurally complex RNA genes that can interact with DNA, RNA or protein molecules to modulate gene expression and to exert cellular effects through diverse mechanisms. The emerging knowledge regarding their functional roles and their aberrant expression in disease states emphasizes the potential for lncRNA to serve as targets for therapeutic intervention. In this concise review, we outline the mechanisms of action of lncRNAs, their functional cellular roles, and their involvement in disease. Using liver cancer as an example, we provide an overview of the emerging opportunities and potential approaches to target lncRNA dependent mechanisms for therapeutic purposes.

Summary Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion and tumorigenicity of MM cells. Moreover, UTX-mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC, and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1. Rebalance of H3K27me3 levels at specific genes through EZH2 inhibitors may be a therapeutic strategy in MM cases harboring UTX mutations.