starBase Pan-Cancer Update: deciphering Pan-Cancer patterns of lncRNAs, ceRNAs, miRNAs and RNA-binding proteins from TCGA 14 cancer types

Posted by lncRNAblog on January 20th, 2014

starBase has been updated to explore Pan-Cancer pattern of lncRNAs, miRNAs, RNA-binding proteins (RBP) and their regulatory networks (ceRNA, coexpression) by mining expression profiles of miRNAs, lncRNAs and mRNAs across 14 cancer types (>6000 samples) from The Cancer Genome Atlas (TCGA) Data Portal (all data available without limitations).

starBase Pan-Cancer analysis is freely available at http://starbase.sysu.edu.cn/panCancer.php

starBase provides the following Pan-Cancer Analysis Services:
1. starBase constructed Pan-Cancer expression profiles of lncRNAs, miRNAs from TCGA RNA-Seq and miRNA-Seq data.
2. starBase generated Pan-Cancer networks of CLIP-Seq experimentally supported miRNA-lncRNA and miRNA-mRNA interactions.
3. starBase identified Pan-Cancer ceRNA networks involving lncRNAs and mRNAs by analyzing >6000 tumor and normal samples and CLIP-Seq suppored miRNA-target interactions.
4. starBase firstly provided Pan-Cancer maps of interactions between RNA-binding proteins (RBPs) and RNAs(lncRNAs, mRNAs).
5. starBase provides interactive BarPlot, ScatterPlot and BoxPlot charts to show the above-mentioned genes and regulatory networks.

This platform will greatly help biologists to explore the impact of lncRNA, miRNA, mRNA, RNA-Binding Protein genes and their regulatory networks on human cancers and other diseases.

Pan-Cancer Analysis Platform

The emerging role of pseudogene expressed non-coding RNAs in cellular functions

Posted by rnablog on May 22nd, 2014

A paradigm shift is sweeping modern day molecular biology following the realisation that large amounts of “junk” DNA”, thought initially to be evolutionary remnants, may actually be functional. Several recent studies support a functional role for pseudogene-expressed non-coding RNAs in regulating their protein-coding counterparts. Several hundreds of pseudogenes have been reported as transcribed into RNA in a large variety of tissues and tumours. Most studies have focused on pseudogenes expressed in the sense direction, but some reports suggest that pseudogenes can also be transcribed as antisense RNAs (asRNAs). A few examples of key regulatory genes, such as PTEN and OCT4, have in fact been reported to be under the regulation of pseudogene-expressed asRNAs. Here, we review what are known about pseudogene expressed non-coding RNA mediated gene regulation and their roles in the control of epigenetic states.

The emerging role of pseudogene expressed non-coding RNAs in cellular functions.
Groen JN1, Capraro D1, Morris KV2.
Int J Biochem Cell Biol. 2014 May 16. [PMID:24842102]

A long noncoding RNA critically regulates Bcr-Abl-mediated cellular transformation by acting as a competitive endogenous RNA

Posted by rnablog on May 22nd, 2014

Aberrant expression of long noncoding RNAs (lncRNAs) is associated with various human cancers. However, the role of lncRNAs in Bcr-Abl-mediated chronic myeloid leukemia (CML) is unknown. In this study, we performed a comprehensive analysis of lncRNAs in human CML cells using an lncRNA cDNA microarray and identified an lncRNA termed lncRNA-BGL3 that acted as a key regulator of Bcr-Abl-mediated cellular transformation. Notably, we observed that lncRNA-BGL3 was highly induced in response to disruption of Bcr-Abl expression or by inhibiting Bcr-Abl kinase activity in K562 cells and leukemic cells derived from CML patients. Ectopic expression of lncRNA-BGL3 sensitized leukemic cells to undergo apoptosis and inhibited Bcr-Abl-induced tumorigenesis. Furthermore, transgenic (TG) mice expressing lncRNA-BGL3 were generated. We found that TG expression of lncRNA-BGL3 alone in mice was sufficient to impair primary bone marrow transformation by Bcr-Abl. Interestingly, we identified that lncRNA-BGL3 was a target of miR-17, miR-93, miR-20a, miR-20b, miR-106a and miR-106b, microRNAs that repress mRNA of phosphatase and tensin homolog (PTEN). Further experiments demonstrated that lncRNA-BGL3 functioned as a competitive endogenous RNA for binding these microRNAs to cross-regulate PTEN expression. Additionally, our experiments have begun to address the mechanism of how lncRNA-BGL3 is regulated in the leukemic cells and showed that Bcr-Abl repressed lncRNA-BGL3 expression through c-Myc-dependent DNA methylation. Taken together, these results reveal that Bcr-Abl-mediated cellular transformation critically requires silence of tumor-suppressor lncRNA-BGL3 and suggest a potential strategy for the treatment of Bcr-Abl-positive leukemia.

A long noncoding RNA critically regulates Bcr-Abl-mediated cellular transformation by acting as a competitive endogenous RNA.
Guo G1, Kang Q1, Zhu X2, Chen Q3, Wang X1, Chen Y1, Ouyang J1, Zhang L4, Tan H5, Chen R6, Huang S7, Chen JL8.
Oncogene. 2014 May 19. [PMID:24837367]

Long noncoding RNAs and prostate carcinogenesis: the missing ‘linc’?

Posted by rnablog on May 22nd, 2014

Long noncoding RNAs (lncRNAs) are rapidly becoming essential pieces in the cancer puzzle. Our understanding of their functional capabilities is in its infancy. One certain fact, however, is that their molecular interactions extend beyond chromatin complexes into diverse biological processes. In prostate cancer, aberrant expression of lncRNAs is associated with disease progression. Overexpression of oncogenic lncRNAs promotes tumor-cell proliferation and metastasis through chromatin looping and distal engagement with the androgen receptor, antisense gene regulation, alternative splicing, and impeding DNA repair. Several lncRNAs, such as prostate cancer antigen 3 (PCA3), prostate cancer gene expression marker 1 (PCGEM1), and prostate cancer associated ncRNA transcript 1 (PCAT1), are highly prostate-specific, posing as attractive biomarkers. Herein we review the mechanisms of action of lncRNAs in prostate carcinogenesis and their potential clinical utility for disease.
Highlights
•At least 6 oncogenic lncRNAs with diverse roles are known in prostate cancer.
•AR addiction is facilitated by lncRNAs in prostate cancer.
•lncRNAs have potential as prognostic prostate cancer biomarkers.

Long noncoding RNAs and prostate carcinogenesis: the missing ‘linc’?Walsh AL1, Tuzova AV2, Bolton EM1, Lynch TH1, Perry AS3.
Walsh AL1, Tuzova AV2, Bolton EM1, Lynch TH1, Perry AS3.
Author information 1Prostate Molecular Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland; Department of Urology, St.
Trends Mol Med. 2014 May 13. [PMID:24836411]

Long intergenic non-coding RNA HOTAIRM1 regulates cell cycle progression during myeloid maturation in NB4 human promyelocytic leukemia cells

Posted by rnablog on May 22nd, 2014

HOTAIRM1 is a long intergenic non-coding RNA encoded in the human HOXA gene cluster, with gene expression highly specific for maturing myeloid cells. Knockdown of HOTAIRM1 in the NB4 acute promyelocytic leukemia cell line retarded all-trans retinoid acid (ATRA)-induced granulocytic differentiation, resulted in significantly larger population of immature and proliferating cells that maintained cell cycle progression from G1 to S phases. Correspondingly, HOTAIRM1 knockdown resulted in retained expression of many otherwise ATRA-suppressed cell cycle and DNA replication genes, and abated ATRA induction of cell surface leukocyte activation, defense response, and other maturation-related genes. Resistance to ATRA-induced cell cycle arrest at the G1/S phase transition in knockdown cells was accompanied by retained expression of ITGA4 (CD49d) and decreased induction of ITGAX (CD11c). The coupling of cell cycle progression with temporal dynamics in the expression patterns of these integrin genes suggests a regulated switch to control the transit from the proliferative phase to granulocytic maturation. Furthermore, ITGAX was among a small number of genes showing perturbation in transcript levels upon HOTAIRM1 knockdown even without ATRA treatment, suggesting a direct pathway of regulation. These results indicate that HOTAIRM1 provides a regulatory link in myeloid maturation by modulating integrin-controlled cell cycle progression at the gene expression level.

Long intergenic non-coding RNA HOTAIRM1 regulates cell cycle progression during myeloid maturation in NB4 human promyelocytic leukemia cells.
Zhang X1, Weissman SM2, Newburger PE3.
RNA Biol. 2014 Apr 24;11(6). [PMID:24824789]

A New Lnc in Metastasis: Long Noncoding RNA Mediates the ProMetastatic Functions of TGF-β

Posted by rnablog on May 22nd, 2014

TGF-β signaling promotes metastasis by controlling the expression of downstream target genes. In this issue of Cancer Cell, Yuan and colleagues discover a novel TGF-β-induced lncRNA, lncRNA-ATB, which stimulates EMT through sequestering miR-200s and facilitates colonization by stabilizing IL-11 mRNA, thus promoting both early and late steps of cancer metastasis.

A New Lnc in Metastasis: Long Noncoding RNA Mediates the ProMetastatic Functions of TGF-β.
Li W1, Kang Y2.
Cancer Cell. 2014 May 12;25(5):557-9. [PMID:24823634]

Biological and bioinformatical approaches to study crosstalk of long-non-coding RNAs and chromatin-modifying proteins

Posted by rnablog on May 22nd, 2014

Long-non-coding RNA (lncRNA) regulates gene expression through transcriptional and epigenetic regulation as well as alternative splicing in the nucleus. In addition, regulation is achieved at the levels of mRNA translation, storage and degradation in the cytoplasm. During recent years, several studies have described the interaction of lncRNAs with enzymes that confer so-called epigenetic modifications, such as DNA methylation, histone modifications and chromatin structure or remodelling. LncRNA interaction with chromatin-modifying enzymes (CME) is an emerging field that confers another layer of complexity in transcriptional regulation. Given that CME-lncRNA interactions have been identified in many biological processes, ranging from development to disease, comprehensive understanding of underlying mechanisms is important to inspire basic and translational research in the future. In this review, we highlight recent findings to extend our understanding about the functional interdependencies between lncRNAs and CMEs that activate or repress gene expression. We focus on recent highlights of molecular and functional roles for CME-lncRNAs and provide an interdisciplinary overview of recent technical and methodological developments that have improved biological and bioinformatical approaches for detection and functional studies of CME-lncRNA interaction.

Biological and bioinformatical approaches to study crosstalk of long-non-coding RNAs and chromatin-modifying proteins.
Backofen R1, Vogel T.
Cell Tissue Res. 2014 May 13. [PMID:24820400]

The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome

Posted by rnablog on May 22nd, 2014

Parental imprinting is a form of epigenetic regulation that results in parent-of-origin differential gene expression. To study Prader-Willi syndrome (PWS), a developmental imprinting disorder, we generated case-derived induced pluripotent stem cells (iPSCs) harboring distinct aberrations in the affected region on chromosome 15. In studying PWS-iPSCs and human parthenogenetic iPSCs, we unexpectedly found substantial upregulation of virtually all maternally expressed genes (MEGs) in the imprinted DLK1-DIO3 locus on chromosome 14. Subsequently, we determined that IPW, a long noncoding RNA in the critical region of the PWS locus, is a regulator of the DLK1-DIO3 region, as its overexpression in PWS and parthenogenetic iPSCs resulted in downregulation of MEGs in this locus. We further show that gene expression changes in the DLK1-DIO3 region coincide with chromatin modifications rather than DNA methylation levels. Our results suggest that a subset of PWS phenotypes may arise from dysregulation of an imprinted locus distinct from the PWS region.

The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome.
Stelzer Y1, Sagi I1, Yanuka O1, Eiges R2, Benvenisty N1.
Nat Genet. 2014 May 11. [PMID:24816254]

lncRNAtor: a comprehensive resource for functional investigation of long noncoding RNAs

Posted by rnablog on May 22nd, 2014

MOTIVATION:A number of long noncoding RNAs (lncRNAs) have been identified by deep sequencing methods, but their molecular and cellular functions are known only for a limited number of lncRNAs. Current databases on lncRNAs are mostly for cataloguing purpose without providing in-depth information required to infer functions. A comprehensive resource on lncRNA function is an immediate need.
RESULTS:We present a database for functional investigation of lncRNAs that encompasses annotation, sequence analysis, gene expression, protein binding, and phylogenetic conservation. We have compiled lncRNAs for 6 species (human, mouse, zebrafish, fruit fly, worm, yeast) from ENSEMBL, HGNC, MGI, and lncRNAdb. Each lncRNA was analyzed for coding potential and phylogenetic conservation in different lineages. Gene expression data of 208 RNA-Seq studies (4995 samples), collected from GEO, ENCODE, modENCODE, and TCGA databases, were used to provide expression profiles in various tissues, diseases, and developmental stages. Importantly, we analyzed RNA-Seq data to identify co-expressed mRNAs that would provide ample insights on lncRNA functions. The resulting gene list can be subject to enrichment analysis such as Gene Ontology or KEGG pathways. Furthermore, we compiled protein-lncRNA interactions by collecting and analyzing publicly available CLIP-seq or PAR-CLIP sequencing data. Finally, we explored evolutionarily conserved lncRNAs with correlated expression between human and six other organisms to identify functional lncRNAs. The whole contents are provided in a user-friendly web interface.AVAILABILITY:
lncRNAtor is available at http://lncrnator.ewha.ac.kr/.

lncRNAtor: a comprehensive resource for functional investigation of long noncoding RNAs.
Park C1, Yu N, Choi I, Kim W, Lee S.
Bioinformatics. 2014 May 9. [PMID:24813212]

FAS-antisense 1 lncRNA and production of soluble versus membrane Fas in B-cell lymphoma

Posted by rnablog on May 12th, 2014

mpaired Fas-mediated apoptosis is associated with poor clinical outcomes and cancer chemoresistance. Soluble Fas receptor (sFas), produced by skipping of exon 6, inhibits apoptosis by sequestering Fas ligand. Serum sFas is associated with poor prognosis of non-Hodgkin’s lymphomas. We found that the alternative splicing of Fas in lymphomas is tightly regulated by a long-noncoding RNA corresponding to an antisense transcript of Fas (FAS-AS1). Levels of FAS-AS1 correlate inversely with production of sFas, and FAS-AS1 binding to the RBM5 inhibits RBM5-mediated exon 6 skipping. EZH2, often mutated or overexpressed in lymphomas, hyper-methylates the FAS-AS1 promoter and represses the FAS-AS1 expression. EZH2-mediated repression of FAS-AS1 promoter can be released by DZNeP (3-Deazaneplanocin A) or overcome by ectopic expression of FAS-AS1, both of which increase levels of FAS-AS1 and correspondingly decrease expression of sFas. Treatment with Bruton’s tyrosine kinase inhibitor or EZH2 knockdown decreases the levels of EZH2, RBM5 and sFas, thereby enhancing Fas-mediated apoptosis. This is the first report showing functional regulation of Fas repression by its antisense RNA. Our results reveal new therapeutic targets in lymphomas and provide a rationale for the use of EZH2 inhibitors or ibrutinib in combination with chemotherapeutic agents that recruit Fas for effective cell killing.

FAS-antisense 1 lncRNA and production of soluble versus membrane Fas in B-cell lymphoma.
Sehgal L, Mathur R, Braun FK, Wise JF, Berkova Z, Neelapu S, Kwak LW, Samaniego F.
Leukemia. 2014 Apr 3. [PMID:24811343]

A long non-coding RNA signature to improve prognosis prediction of colorectal cancer

Posted by rnablog on May 11th, 2014

Increasing evidence suggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, few related lncRNA signatures have been established for prediction of cancer prognosis. We aimed to develop a lncRNA signature to improve prognosis prediction of colorectal cancer (CRC). Using a lncRNA-mining approach, we performed lncRNA expression profiling in large CRC cohorts from Gene Expression Ominus (GEO), including GSE39582 test series(N=436), internal validation series (N=117); and two independent validation series GSE14333 (N=197) and GSE17536(N=145). We established a set of six lncRNAs that were significantly correlated with the disease free survival (DFS) in the test series. Based on this six-lncRNA signature, the test series patients could be classified into high-risk and low-risk subgroups with significantly different DFS (HR=2.670; P<0.0001). The prognostic value of this six-lncRNA signature was confirmed in the internal validation series and another two independent CRC sets. Gene set enrichment analysis (GSEA) analysis suggested that risk score positively correlated with several cancer metastasis related pathways. Functional experiments demonstrated three dysregulated lncRNAs, AK123657, BX648207 and BX649059 were required for efficient invasion and proliferation suppression in CRC cell lines. Our results might provide an efficient classification tool for clinical prognosis evaluation of CRC.

A long non-coding RNA signature to improve prognosis prediction of colorectal cancer.
Hu Y1, Chen HY, Yu CY, Xu J, Wang JL, Qian J, Zhang X, Fang JY.
Oncotarget. 2014 Apr 30;5(8):2230-42. [PMID:24809982]


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