Long noncoding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes including cancer. To delineate genome-wide lncRNA expression, we curated 7,256 RNA ...sequencing (RNA-seq) libraries from tumors, normal tissues and cell lines comprising over 43 Tb of sequence from 25 independent studies. We applied ab initio assembly methodology to this data set, yielding a consensus human transcriptome of 91,013 expressed genes. Over 68% (58,648) of genes were classified as lncRNAs, of which 79% were previously unannotated. About 1% (597) of the lncRNAs harbored ultraconserved elements, and 7% (3,900) overlapped disease-associated SNPs. To prioritize lineage-specific, disease-associated lncRNA expression, we employed non-parametric differential expression testing and nominated 7,942 lineage- or cancer-associated lncRNA genes. The lncRNA landscape characterized here may shed light on normal biology and cancer pathogenesis and may be valuable for future biomarker development.
During epithelial-mesenchymal transition (EMT) epithelial cancer cells transdifferentiate into highly motile, invasive, mesenchymal-like cells, giving rise to disseminating tumor cells. Few of these ...disseminated cells successfully metastasize. Immune cells and inflammation in the tumor microenvironment were shown to drive EMT, but few studies investigated the consequences of EMT for tumor immunosurveillance. In addition to initiating metastasis, we demonstrate that EMT confers increased susceptibility to natural killer (NK) cells and contributes, in part, to the inefficiency of the metastatic process. Depletion of NK cells allowed spontaneous metastasis without affecting primary tumor growth. EMT-induced modulation of E-cadherin and cell adhesion molecule 1 (CADM1) mediated increased susceptibility to NK cytotoxicity. Higher CADM1 expression correlates with improved patient survival in 2 lung and 1 breast adenocarcinoma patient cohorts and decreased metastasis. Our observations reveal a novel NK-mediated, metastasis-specific immunosurveillance in lung cancer and present a window of opportunity for preventing metastasis by boosting NK cell activity.
A formulation of infinite NURBS patches is presented which allows the modeling of infinite surfaces with the NURBS based boundary element method. Applications are the modeling of long tunnels and of ...the ground surface in geotechnical work. To achieve an infinite surface, special mapping functions are used for describing the geometry. For the description of the displacements either a constant variation is assumed simulating plane strain conditions or it is assumed that the displacements decay to zero at infinity. The theory and implementation details are presented. Test examples show that the proposed formulation works well for the simulation of long tunnels and of the ground surface. Finally a practical example of a tunnel intersection is presented.
Activation of normally silent tissue-specific genes and the resulting cell "identity crisis" are the unexplored consequences of malignant epigenetic reprogramming. We designed a strategy for ...investigating this reprogramming, which consisted of identifying a large number of tissue-restricted genes that are epigenetically silenced in normal somatic cells and then detecting their expression in cancer. This approach led to the demonstration that large-scale "off-context" gene activations systematically occur in a variety of cancer types. In our series of 293 lung tumors, we identified an ectopic gene expression signature associated with a subset of highly aggressive tumors, which predicted poor prognosis independently of the TNM (tumor size, node positivity, and metastasis) stage or histological subtype. The ability to isolate these tumors allowed us to reveal their common molecular features characterized by the acquisition of embryonic stem cell/germ cell gene expression profiles and the down-regulation of immune response genes. The methodical recognition of ectopic gene activations in cancer cells could serve as a basis for gene signature-guided tumor stratification, as well as for the discovery of oncogenic mechanisms, and expand the understanding of the biology of very aggressive tumors.
The long noncoding RNA (lncRNA)
has previously been identified as a prognostic marker in hepatocellular carcinoma. Here, we performed a comprehensive analysis of lncRNA expression profiles from ...RNA-Seq data and report that
plays a similar role in lung cancer. Analysis of 918 lung cancer and normal lung tissues and lung cancer cell lines revealed that
was significantly downregulated in lung cancer; this decreased expression was associated with poor patient survival.
bound and stabilized the YBX1 protein. Silencing of
triggered both cell survival and cell death signaling through dysregulation of the oncogenes YBX1, MET, and p21. In this
network, p21 played an oncogenic role by promoting cell proliferation and antiapoptosis in lung cancers.
played a tumor-suppressive role as indicated by inhibition of multiple cell cycle-related genes in human primary lung tumors. These data show that
has potential as a new diagnostic and prognostic marker and as a therapeutic target for lung cancer.
The lncRNA
functions as a tumor suppressor, with potential use a diagnostic/prognostic marker and therapeutic target in lung cancer.
.
To identify stage I lung adenocarcinoma patients with a poor prognosis who will benefit from adjuvant therapy.
Whole gene expression profiles were obtained at 19 time points over a 48-hour time ...course from human primary lung epithelial cells that were stimulated with epidermal growth factor (EGF) in the presence or absence of a clinically used EGF receptor tyrosine kinase (RTK)-specific inhibitor, gefitinib. The data were subjected to a mathematical simulation using the State Space Model (SSM). "Gefitinib-sensitive" genes, the expressional dynamics of which were altered by addition of gefitinib, were identified. A risk scoring model was constructed to classify high- or low-risk patients based on expression signatures of 139 gefitinib-sensitive genes in lung cancer using a training data set of 253 lung adenocarcinomas of North American cohort. The predictive ability of the risk scoring model was examined in independent cohorts of surgical specimens of lung cancer.
The risk scoring model enabled the identification of high-risk stage IA and IB cases in another North American cohort for overall survival (OS) with a hazard ratio (HR) of 7.16 (P = 0.029) and 3.26 (P = 0.0072), respectively. It also enabled the identification of high-risk stage I cases without bronchioalveolar carcinoma (BAC) histology in a Japanese cohort for OS and recurrence-free survival (RFS) with HRs of 8.79 (P = 0.001) and 3.72 (P = 0.0049), respectively.
The set of 139 gefitinib-sensitive genes includes many genes known to be involved in biological aspects of cancer phenotypes, but not known to be involved in EGF signaling. The present result strongly re-emphasizes that EGF signaling status in cancer cells underlies an aggressive phenotype of cancer cells, which is useful for the selection of early-stage lung adenocarcinoma patients with a poor prognosis.
The Gene Expression Omnibus (GEO) GSE31210.
Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. ...Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.
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•THOR is a conserved lncRNA expressed in cancers and in normal testis•THOR functions via a conserved interaction with IGF2BP1, stabilizing its targets•Oncogenicity of THOR is corroborated in a zebrafish model
An ultraconserved lncRNA promotes oncogenesis.
The influence of the grain size on the flow stress of extruded Mg–3Al–1Zn tested in compression is examined. Samples with grain sizes varying between 3 and 23 μm were prepared by altering the ...extrusion conditions. Compression testing of the extruded bar was carried out at temperatures between ambient and 200 °C. Twinning dominated the deformation at lower temperatures but this gave way to slip dominated flow when the temperature was raised. For tests carried out at intermediate temperatures, a similar transition was observed when the grain size was reduced. The transition was accompanied by a change in flow curve shape and Hall–Petch slope. The peak stresses achieved when twinning dominated the deformation were up to 100 MPa greater than those seen when slip dominated the flow. Critical grain sizes marking the twinning–slip transition were identified and these are described in terms of the deformation conditions.
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