Construction of a lncRNA-PCG bipartite network and identification of cancer-related lncRNAs: a case study in prostate cancer.

LncRNAs are involved in a wide range of biological processes, such as chromatin remodeling, mRNA splicing, mRNA editing and translation. They can either upregulate or downregulate gene expression, and play key roles in the progression of various human cancers. However, the functional mechanisms of most lncRNAs still remain unknown at present. This paper aims to provide space for the understanding of lncRNAs by proposing a new method to obtain protein-coding genes (PCGs) regulated by lncRNAs, thus identifying candidate cancer-related lncRNAs using bioinformatics approaches. This study presents a method based on sample correlation, which is applied to the expression profiles of lncRNAs and PCGs in prostate cancer in combination with protein interaction data to build a lncRNA-PCG bipartite network. Candidate cancer-related lncRNAs were extracted from the bipartite network by using a random walk. 14 prostate cancer-related lncRNAs were acquired from the LncRNADisease database and MNDR, of which 6 lncRNAs were present in our network. As one of the seed nodes, ENSG00000234741 achieved the highest score among them. The other two cancer-related lncRNAs (ENSG00000225937 and ENSG00000236830) were ranked within the top 30. In addition, the top candidate lncRNA ENSG00000261777 shares an intron with DDX19, and interacts with IGF2 P1, indicating its involvement in prostate cancer. In this paper, we described a new method for predicting candidate lncRNA targets, and obtained candidate therapeutic targets using this method. We hope that this study will bring a new perspective in future lncRNA studies.

[1]  P. Robinson,et al.  Walking the interactome for prioritization of candidate disease genes. , 2008, American journal of human genetics.

[2]  Christian Ruiz,et al.  Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients , 2014, Hepatology.

[3]  Yoshihiro Yamanishi,et al.  Extraction of correlated gene clusters from multiple genomic data by generalized kernel canonical correlation analysis , 2003, ISMB.

[4]  Yadong Wang,et al.  Prioritization of disease microRNAs through a human phenome-microRNAome network , 2010, BMC Systems Biology.

[5]  Anna L. Walsh,et al.  Noncoding RNAs in Prostate Cancer: The Long and the Short of It , 2013, Clinical Cancer Research.

[6]  T. Morgan,et al.  Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase , 2008, Nature Medicine.

[7]  M. Caetano,et al.  PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling , 2012, BMC Cancer.

[8]  Kathleen C Insel,et al.  High Perceived Stress Is Linked to Afternoon Cortisol Levels and Greater Symptom Distress in Patients With Localized Prostate Cancer , 2011, Cancer nursing.

[9]  M. Karin,et al.  Tumor infiltrating B-cells are increased in prostate cancer tissue , 2014, Journal of Translational Medicine.

[10]  E. Rimm,et al.  Height, predictors of C-peptide and cancer risk in men. , 2004, International journal of epidemiology.

[11]  Emily A. Vucic,et al.  Human Cancer Long Non-Coding RNA Transcriptomes , 2011, PloS one.

[12]  J. Mattick,et al.  Long non-coding RNAs: insights into functions , 2009, Nature Reviews Genetics.

[13]  Hae-Young Kim.  Statistical notes for clinical researchers: assessing normal distribution (2) using skewness and kurtosis , 2013, Restorative dentistry & endodontics.

[14]  Y. Wang,et al.  Mammalian ncRNA-disease repository: a global view of ncRNA-mediated disease network , 2013, Cell Death and Disease.

[15]  C. Tsai-Morris,et al.  Gonadotropin-regulated testicular helicase (GRTH/DDX25): an essential regulator of spermatogenesis , 2007, Trends in Endocrinology & Metabolism.

[16]  Y. Tu,et al.  Quantitative noise analysis for gene expression microarray experiments , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Wei Huang,et al.  Insulin‐like growth factor‐2 (IGF2) loss of imprinting marks a field defect within human prostates containing cancer , 2011, The Prostate.

[18]  Olivier Voinnet,et al.  The long and the short of noncoding RNAs. , 2009, Current opinion in cell biology.

[19]  H. Kung,et al.  Statins and prostate cancer: role of cholesterol inhibition vs. prevention of small GTP-binding proteins. , 2011, American journal of cancer research.

[20]  C. Ponting,et al.  Genomic and Transcriptional Co-Localization of Protein-Coding and Long Non-Coding RNA Pairs in the Developing Brain , 2009, PLoS genetics.

[21]  Tsviya Olender,et al.  GeneCards Version 3: the human gene integrator , 2010, Database J. Biol. Databases Curation.

[22]  S. P. Fodor,et al.  Large-Scale Transcriptional Activity in Chromosomes 21 and 22 , 2002, Science.

[23]  Mike Tyers,et al.  BioGRID: a general repository for interaction datasets , 2005, Nucleic Acids Res..

[24]  Zhen Su,et al.  Integrative genomic analyses reveal clinically relevant long non-coding RNA in human cancer , 2013 .

[25]  Chunquan Li,et al.  CNVD: Text mining‐based copy number variation in disease database , 2012, Human mutation.

[26]  T. Derrien,et al.  Long Noncoding RNAs with Enhancer-like Function in Human Cells , 2010, Cell.

[27]  F. Markowetz,et al.  The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups , 2012, Nature.

[28]  James L Mohler,et al.  Activated tyrosine kinase Ack1 promotes prostate tumorigenesis: role of Ack1 in polyubiquitination of tumor suppressor Wwox. , 2005, Cancer research.

[29]  Lars Feuk,et al.  The Database of Genomic Variants: a curated collection of structural variation in the human genome , 2013, Nucleic Acids Res..

[30]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[31]  M. Irwin,et al.  Post-traumatic disorder symptoms and blunted diurnal cortisol production in partners of prostate cancer patients , 2012, Psychoneuroendocrinology.

[32]  M. Gleave,et al.  IGF2 increases de novo steroidogenesis in prostate cancer cells. , 2013, Endocrine-related cancer.

[33]  Shuli Kang,et al.  Large-scale prediction of long non-coding RNA functions in a coding–non-coding gene co-expression network , 2011, Nucleic acids research.

[34]  Jingsong Yuan,et al.  FIGNL1-containing protein complex is required for efficient homologous recombination repair , 2013, Proceedings of the National Academy of Sciences.

[35]  Cole Trapnell,et al.  Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. , 2011, Genes & development.

[36]  Xing Chen,et al.  LncRNADisease: a database for long-non-coding RNA-associated diseases , 2012, Nucleic Acids Res..

[37]  Ke Liu,et al.  Linc2GO: a human LincRNA function annotation resource based on ceRNA hypothesis , 2013, Bioinform..

[38]  M. Gleave,et al.  Insulin increases de novo steroidogenesis in prostate cancer cells. , 2011, Cancer research.

[39]  Howard Y. Chang,et al.  A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression , 2011, Nature.

[40]  D. Spector,et al.  Long noncoding RNAs: functional surprises from the RNA world. , 2009, Genes & development.

[41]  Hedi Peterson,et al.  g:Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments , 2007, Nucleic Acids Res..

[42]  Gajendra P. S. Raghava,et al.  lncRNome: a comprehensive knowledgebase of human long noncoding RNAs , 2013, Database J. Biol. Databases Curation.

[43]  Eliot Marshall,et al.  Getting the Noise Out of Gene Arrays , 2004, Science.

[44]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Yi Zhang,et al.  Role of H3K27 methylation in the regulation of lncRNA expression , 2010, Cell Research.

[46]  Kristopher Attwood,et al.  RhoA as a mediator of clinically relevant androgen action in prostate cancer cells. , 2012, Molecular endocrinology.

[47]  J. Weigelt,et al.  The DEXD/H-box RNA Helicase DDX19 Is Regulated by an α-Helical Switch*S⃞ , 2009, Journal of Biological Chemistry.

[48]  Lang Li,et al.  High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia. , 2003, The American journal of pathology.

[49]  S. Chua,et al.  Prostate cancer risk and serum levels of insulin and leptin: a population-based study. , 2001, Journal of the National Cancer Institute.

[50]  Sylvain V Costes,et al.  Automatic and quantitative measurement of protein-protein colocalization in live cells. , 2004, Biophysical journal.

[51]  H. Wakelee,et al.  Ramucirumab, a fully human mAb to the transmembrane signaling tyrosine kinase VEGFR-2 for the potential treatment of cancer. , 2009, Current opinion in investigational drugs.

[52]  F. Costa,et al.  Non‐coding RNAs: Meet thy masters , 2010, BioEssays : news and reviews in molecular, cellular and developmental biology.

[53]  H. Kung,et al.  A tyrosine kinase profile of prostate carcinoma. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[54]  E. Greer,et al.  Histone methylation: a dynamic mark in health, disease and inheritance , 2012, Nature Reviews Genetics.

[55]  M. Mann,et al.  N-linked Glycosylation Enrichment for In-depth Cell Surface Proteomics of Diffuse Large B-cell Lymphoma Subtypes* , 2013, Molecular & Cellular Proteomics.

[56]  Beth Israel,et al.  Decision letter: Replication Study: A coding-independent function of gene and pseudogene mRNAs regulates tumour biology , 2010 .

[57]  S. Shabalina,et al.  The mammalian transcriptome and the function of non-coding DNA sequences , 2004, Genome Biology.

[58]  S. Pittaluga,et al.  Ibrutinib inhibits BCR and NF-κB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. , 2014, Blood.

[59]  J. Byrd,et al.  Epigenetic changes during disease progression in a murine model of human chronic lymphocytic leukemia , 2009, Proceedings of the National Academy of Sciences.

[60]  A. Yakovlev,et al.  How high is the level of technical noise in microarray data? , 2007, Biology Direct.