A global microRNA screen identifies regulators of the ErbB receptor signaling network

Background: The growth factor heregulin (HRG) potently stimulates epithelial cell survival and proliferation through the binding of its cognate receptor ErbB3 (also known as HER3). ErbB3-dependent signal transmission relies on the dimerization partner ErbB2, a receptor tyrosine kinase that is frequently overexpressed and/or amplified in breast cancer cells. Substantial evidence suggests that deregulated ErbB3 expression also contributes to the transformed phenotype of breast cancer cells. Results: By genome-wide screening, we identify 43 microRNAs (miRNAs) that specifically impact HRG-induced activation of the PI3K-Akt pathway. Bioinformatic analysis combined with experimental validation reveals a highly connected molecular miRNA-gene interaction network particularly for the negative screen hits. For selected miRNAs, namely miR-149, miR-148b, miR-326, and miR-520a-3p, we demonstrate the simultaneous downregulation of the ErbB3 receptor and multiple downstream signaling molecules, explaining their efficient dampening of HRG responses and ascribing to these miRNAs potential context-dependent tumor suppressive functions. Conclusions: Given the contribution of HRG signaling and the PI3K-Akt pathway in particular to tumorigenesis, this study not only provides mechanistic insight into the function of miRNAs but also has implications for future clinical applications

Carcinoma cells misuse the host tissue damage response to invade the brain

The metastatic colonization of the brain by carcinoma cells is still barely understood, in particular when considering interactions with the host tissue. The colonization comes with a substantial destruction of the surrounding host tissue. This leads to activation of damage responses by resident innate immune cells to protect, repair, and organize the wound healing, but may distract from tumoricidal actions. We recently demonstrated that microglia, innate immune cells of the CNS, assist carcinoma cell invasion. Here we report that this is a fatal side effect of a physiological damage response of the brain tissue. In a brain slice coculture model, contact with both benign and malignant epithelial cells induced a response by microglia and astrocytes comparable to that seen at the interface of human cerebral metastases. While the glial damage response intended to protect the brain from intrusion of benign epithelial cells by inducing apoptosis, it proved ineffective against various malignant cell types. They did not undergo apoptosis and actually exploited the local tissue reaction to invade instead. Gene expression and functional analyses revealed that the C-X-C chemokine receptor type 4 (CXCR4) and WNT signaling were involved in this process. Furthermore, CXCR4-regulated microglia were recruited to sites of brain injury in a zebrafish model and CXCR4 was expressed in human stroke patients, suggesting a conserved role in damage responses to various types of brain injuries. Together, our findings point to a detrimental misuse of the glial damage response program by carcinoma cells resistant to glia-induced apoptosis

R-Based Software for the Integration of Pathway Data into Bioinformatic Algorithms

Putting new findings into the context of available literature knowledge is one approach to deal with the surge of high-throughput data results. Furthermore, prior knowledge can increase the performance and stability of bioinformatic algorithms, for example, methods for network reconstruction. In this review, we examine software packages for the statistical computing framework R, which enable the integration of pathway data for further bioinformatic analyses. Different approaches to integrate and visualize pathway data are identified and packages are stratified concerning their features according to a number of different aspects: data import strategies, the extent of available data, dependencies on external tools, integration with further analysis steps and visualization options are considered. A total of 12 packages integrating pathway data are reviewed in this manuscript. These are supplemented by five R-specific packages for visualization and six connector packages, which provide access to external tools

New World Arenavirus Z protein alignment

Alignment of the Z protein of 51 NWA sequences, labelled with Genbank accessions numbers

Data from: Complex patterns of host switching in New World Arenaviruses

We empirically tested the long-standing hypothesis of codivergence of New World arenaviruses (NWA) with their hosts. We constructed phylogenies for NWA and all known hosts and used them in reconciliation analyses. We also constructed a phylogenetic tree of all Sigmodontinae and Neotominae rodents and tested whether viral–host associations were phylogenetically clustered. We determined host geographical overlap to determine to what extent opportunity to switch hosts was limited by host relatedness or physical proximity. With the exception of viruses from North America, no phylogenetically codivergent pattern between NWA and their hosts was found. We found that different virus clades were clustered differently and that Clade B with members pathogenic to humans was randomly distributed across the rodent phylogeny. Furthermore, viral relatedness within Clade B was significantly explained by the geographic overlap of their hosts’ ranges rather than host relatedness, indicating that they are capable of host switching opportunistically. This has important bearings on their potential to become panzootic. Together, these analyses suggest that NWA have not codiverged with their hosts and instead have evolved predominantly via host switching

Correction: A comparative study of RNA-Seq and microarray data analysis on the two examples of rectal-cancer patients and Burkitt Lymphoma cells.

[This corrects the article DOI: 10.1371/journal.pone.0197162.]

New World Arenavirus -Nucleoprotien alignment

Alignment of the nucleoprotien of 64 NWA sequences, labelled with Genbank accessions numbers

Sigmodontinae and Neotominae Mitochondria Cytochrome B alignment

Sigmodontinae and Neotominae Mitochondria Cytochrome B alignment. 523 taxa aligned with Genbank accession number and current taxonomy indicated for each sequence

New World Arenavirus -L protein alignment

Alignment of the L protein of 37 NWA sequences, labelled with Genbank accessions numbers