The regulatory network analysis of long noncoding RNAs in human colorectal cancer

Colorectal cancer (CRC) is among one of the most prevalent and lethiferous diseases worldwide. Long noncoding RNAs (lncRNAs) are commonly accepted to function as a key regulatory factor in human cancer, but the potential regulatory mechanisms of CRC-associated lncRNA are largely obscure. Here, we integrated several expression profiles to obtain 55 differentially expressed (DE) lncRNAs. We first detected lncRNA interactions with transcription factors, microRNAs, mRNAs, and RNA-binding proteins to construct a regulatory network and then create functional enrichment analyses for them using bioinformatics approaches. We found the upregulated genes in the regulatory network are enriched in cell cycle and DNA damage response, while the downregulated genes are enriched in cell differentiation, cellular response, and cell signaling. We then employed module-based methods to mine several intriguing modules from the overall network, which helps to classify the functions of genes more specifically. Next, we confirmed the validity of our network by comparisons with a randomized network using computational method. Finally, we attempted to annotate lncRNA functions based on the regulatory network, which indicated its potential application. Our study of the lncRNA regulatory network provided significant clues to unveil lncRNAs potential regulatory mechanisms in CRC and laid a foundation for further experimental investigation.

[1]  Hua,et al.  Identification of , 2000, Journal of insect physiology.

[2]  Gary D. Bader,et al.  An automated method for finding molecular complexes in large protein interaction networks , 2003, BMC Bioinformatics.

[3]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[4]  Gene Ontology Consortium The Gene Ontology (GO) database and informatics resource , 2003 .

[5]  Gregory D. Schuler,et al.  Database resources of the National Center for Biotechnology , 2003, Nucleic Acids Res..

[6]  Christian von Mering,et al.  STRING: a database of predicted functional associations between proteins , 2003, Nucleic Acids Res..

[7]  Anton J. Enright,et al.  Human MicroRNA Targets , 2004, PLoS biology.

[8]  Kimberly Van Auken,et al.  WormBase: a multi-species resource for nematode biology and genomics , 2004, Nucleic Acids Res..

[9]  L. Shaffer,et al.  Allele-specific methylation of a functional CTCF binding site upstream of MEG3 in the human imprinted domain of 14q32 , 2005, Chromosome Research.

[10]  D. Monté,et al.  H19 mRNA-like Noncoding RNA Promotes Breast Cancer Cell Proliferation through Positive Control by E2F1* , 2005, Journal of Biological Chemistry.

[11]  M. Bartolomei,et al.  CTCF binding sites promote transcription initiation and prevent DNA methylation on the maternal allele at the imprinted H19/Igf2 locus. , 2006, Human molecular genetics.

[12]  D. Krag,et al.  Combination treatment with Grb7 peptide and Doxorubicin or Trastuzumab (Herceptin) results in cooperative cell growth inhibition in breast cancer cells , 2007, British Journal of Cancer.

[13]  William Stafford Noble,et al.  Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project , 2007, Nature.

[14]  Luigi Naldini,et al.  Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state , 2007, Nature Biotechnology.

[15]  Stijn van Dongen,et al.  miRBase: tools for microRNA genomics , 2007, Nucleic Acids Res..

[16]  Jiri Bartek,et al.  An Oncogene-Induced DNA Damage Model for Cancer Development , 2008, Science.

[17]  S. Batzoglou,et al.  Genome-Wide Analysis of Transcription Factor Binding Sites Based on ChIP-Seq Data , 2008, Nature Methods.

[18]  R. Aguiar,et al.  Copy number abnormalities, MYC activity, and the genetic fingerprint of normal B cells mechanistically define the microRNA profile of diffuse large B-cell lymphoma. , 2009, Blood.

[19]  J. Disterhoft,et al.  Balanced gene regulation by an embryonic brain ncRNA is critical for adult hippocampal GABA circuitry. , 2009, Nature neuroscience.

[20]  M. Barbacid,et al.  Cell cycle, CDKs and cancer: a changing paradigm , 2009, Nature Reviews Cancer.

[21]  G. Chrousos,et al.  Noncoding RNA Gas5 Is a Growth Arrest– and Starvation-Associated Repressor of the Glucocorticoid Receptor , 2010, Science Signaling.

[22]  Mary Goldman,et al.  The UCSC Genome Browser database: update 2011 , 2010, Nucleic Acids Res..

[23]  T. Tamura,et al.  Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts. , 2011, RNA.

[24]  Cedric E. Ginestet ggplot2: Elegant Graphics for Data Analysis , 2011 .

[25]  Kotb Abdelmohsen,et al.  LincRNA-p21 suppresses target mRNA translation. , 2012, Molecular cell.

[26]  Data production leads,et al.  An integrated encyclopedia of DNA elements in the human genome , 2012 .

[27]  ENCODEConsortium,et al.  An Integrated Encyclopedia of DNA Elements in the Human Genome , 2012, Nature.

[28]  Guangchuang Yu,et al.  clusterProfiler: an R package for comparing biological themes among gene clusters. , 2012, Omics : a journal of integrative biology.

[29]  Sean R. Davis,et al.  NCBI GEO: archive for functional genomics data sets—update , 2012, Nucleic Acids Res..

[30]  J. Foekens,et al.  CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer , 2013, Genome research.

[31]  Jianming Xu,et al.  Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  Petr Klus,et al.  catRAPID omics: a web server for large-scale prediction of protein–RNA interactions , 2013, Bioinform..

[33]  James E. DiCarlo,et al.  RNA-Guided Human Genome Engineering via Cas9 , 2013, Science.

[34]  Hanfei Sun,et al.  Target analysis by integration of transcriptome and ChIP-seq data with BETA , 2013, Nature Protocols.

[35]  Insulin-Like Growth Factor-1 Modulates Polycomb Cbx8 Expression and Inhibits Colon Cancer Cell Apoptosis , 2015, Cell Biochemistry and Biophysics.

[36]  Y. Sang,et al.  Paradoxical role of CBX8 in proliferation and metastasis of colorectal cancer , 2014, Oncotarget.

[37]  Anindya Dutta,et al.  The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration , 2014, Genes & development.

[38]  Limei Ma,et al.  C-Myc-activated long noncoding RNA CCAT1 promotes colon cancer cell proliferation and invasion , 2014, Tumor Biology.

[39]  D. Speiser,et al.  T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? , 2014, Nature Reviews Immunology.

[40]  R. Carrio,et al.  Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice , 2014, Front. Physiol..

[41]  J. Cai,et al.  HOTAIR: a cancer-related long non-coding RNA. , 2014, Neoplasma.

[42]  Jia Yu,et al.  Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate gastric cancer progression , 2015, Journal of experimental & clinical cancer research : CR.

[43]  Jonathan van Eyll,et al.  Pathway analysis from lists of microRNAs: common pitfalls and alternative strategy , 2015, Nucleic acids research.

[44]  Long non-coding RNA Loc554202 induces apoptosis in colorectal cancer cells via the caspase cleavage cascades , 2015, Journal of experimental & clinical cancer research : CR.

[45]  Ahmedin Jemal,et al.  Global Cancer Incidence and Mortality Rates and Trends—An Update , 2015, Cancer Epidemiology, Biomarkers & Prevention.

[46]  Steven J. M. Jones,et al.  MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA–DNA triplex structures , 2015, Nature Communications.

[47]  B. Herrmann,et al.  Mechanisms of long noncoding RNA function in development and disease , 2016, Cellular and Molecular Life Sciences.

[48]  Jing Lin,et al.  Long non-coding RNA MEG3 inhibits microRNA-125a-5p expression and induces immune imbalance of Treg/Th17 in immune thrombocytopenic purpura. , 2016, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[49]  P. Wei,et al.  A Positive Feedback Loop of lncRNA-PVT1 and FOXM1 Facilitates Gastric Cancer Growth and Invasion , 2016, Clinical Cancer Research.

[50]  M. Kretz,et al.  Long non-coding RNA ZFAS1 interacts with CDK1 and is involved in p53-dependent cell cycle control and apoptosis in colorectal cancer , 2015, OncoTarget.

[51]  B. Erman,et al.  Long noncoding RNA (lincRNA), a new paradigm in gene expression control , 2016, Functional & Integrative Genomics.

[52]  Chun-Ying Yu,et al.  The Trans‐Spliced Long Noncoding RNA tsRMST Impedes Human Embryonic Stem Cell Differentiation Through WNT5A‐Mediated Inhibition of the Epithelial‐to‐Mesenchymal Transition , 2016, Stem cells.

[53]  Min Zhang,et al.  Long noncoding RNA SNHG1 predicts a poor prognosis and promotes hepatocellular carcinoma tumorigenesis. , 2016, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[54]  Yong Guo,et al.  Integrated analysis of long non-coding RNAs in human colorectal cancer , 2016, Oncotarget.

[55]  Ahmedin Jemal,et al.  Global patterns and trends in colorectal cancer incidence and mortality , 2016, Gut.

[56]  Xu Gao,et al.  Long noncoding RNA H19 indicates a poor prognosis of colorectal cancer and promotes tumor growth by recruiting and binding to eIF4A3 , 2016, Oncotarget.

[57]  Dan Zhao,et al.  Clinical significance of HOTAIR expression in colon cancer. , 2016, World journal of gastroenterology.

[58]  Zhaohui Tang,et al.  Long non-coding RNA H19 regulates FOXM1 expression by competitively binding endogenous miR-342-3p in gallbladder cancer , 2016, Journal of Experimental & Clinical Cancer Research.

[59]  Rodolfo Ghirlando,et al.  CTCF: making the right connections , 2016, Genes & development.

[60]  Jianrong Li,et al.  Cancer RNA-Seq Nexus: a database of phenotype-specific transcriptome profiling in cancer cells , 2015, Nucleic Acids Res..

[61]  A. Bayoumi,et al.  Crosstalk between Long Noncoding RNAs and MicroRNAs in Health and Disease , 2016, International journal of molecular sciences.

[62]  Tao Chen,et al.  Long noncoding RNA GAPLINC promotes invasion in colorectal cancer by targeting SNAI2 through binding with PSF and NONO , 2016, Oncotarget.

[63]  Yijun Yang,et al.  UCA1 functions as a competing endogenous RNA to suppress epithelial ovarian cancer metastasis , 2016, Tumor Biology.

[64]  B. Wang,et al.  Long non-coding RNA PVT1 promotes glycolysis and tumor progression by regulating miR-497/HK2 axis in osteosarcoma. , 2017, Biochemical and biophysical research communications.

[65]  Hao Guo,et al.  The long non-coding RNA HOTAIR promotes thyroid cancer cell growth, invasion and migration through the miR-1-CCND2 axis. , 2017, American journal of cancer research.

[66]  Jie Hong,et al.  Differentially Expressed lncRNAs in Gastric Cancer Patients: A Potential Biomarker for Gastric Cancer Prognosis , 2017, Journal of Cancer.

[67]  A. Jemal,et al.  Colorectal cancer statistics, 2017 , 2017, CA: a cancer journal for clinicians.

[68]  O. Barbier,et al.  Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay , 2017, Hepatology.

[69]  P. Zhou,et al.  Upregulation of the long non-coding RNA SNHG1 predicts poor prognosis, promotes cell proliferation and invasion, and reduces apoptosis in glioma. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[70]  Xin Wang,et al.  H19 promotes the migration and invasion of colon cancer by sponging miR-138 to upregulate the expression of HMGA1. , 2017, International journal of oncology.

[71]  Lixia Li,et al.  MEG3 is a prognostic factor for CRC and promotes chemosensitivity by enhancing oxaliplatin-induced cell apoptosis , 2017, Oncology reports.

[72]  He Li,et al.  Roles of long noncoding RNAs in colorectal cancer metastasis , 2017, Oncotarget.

[73]  J. Mazar,et al.  The long non-coding RNA GAS5 differentially regulates cell cycle arrest and apoptosis through activation of BRCA1 and p53 in human neuroblastoma , 2016, Oncotarget.

[74]  Yun Bai,et al.  Long noncoding RNA expression profiles in chondrogenic and hypertrophic differentiation of mouse mesenchymal stem cells , 2017, Functional & Integrative Genomics.

[75]  Yuwei Zhang,et al.  Long noncoding RNA: a crosslink in biological regulatory network , 2018, Briefings Bioinform..

[76]  Guozhang Ma,et al.  Long Noncoding RNA PVT1 Promotes Melanoma Progression via Endogenous Sponging miR-26b. , 2017, Oncology research.

[77]  Evan Bolton,et al.  Database resources of the National Center for Biotechnology Information , 2017, Nucleic Acids Res..