LncRNA profile study reveals a three-lncRNA signature associated with the survival of patients with oesophageal squamous cell carcinoma

Background Oesophageal cancer is one of the most deadly forms of cancer worldwide. Long non-coding RNAs (lncRNAs) are often found to have important regulatory roles. Objective To assess the lncRNA expression profile of oesophageal squamous cell carcinoma (OSCC) and identify prognosis-related lncRNAs. Method LncRNA expression profiles were studied by microarray in paired tumour and normal tissues from 119 patients with OSCC and validated by qRT-PCR. The 119 patients were divided randomly into training (n=60) and test (n=59) groups. A prognostic signature was developed from the training group using a random Forest supervised classification algorithm and a nearest shrunken centroid algorithm, then validated in a test group and further, in an independent cohort (n=60). The independence of the signature in survival prediction was evaluated by multivariable Cox regression analysis. Results LncRNAs showed significantly altered expression in OSCC tissues. From the training group, we identified a three-lncRNA signature (including the lncRNAs ENST00000435885.1, XLOC_013014 and ENST00000547963.1) which classified the patients into two groups with significantly different overall survival (median survival 19.2 months vs >60 months, p<0.0001). The signature was applied to the test group (median survival 21.5 months vs >60 months, p=0.0030) and independent cohort (median survival 25.8 months vs >48 months, p=0.0187) and showed similar prognostic values in both. Multivariable Cox regression analysis showed that the signature was an independent prognostic factor for patients with OSCC. Stratified analysis suggested that the signature was prognostic within clinical stages. Conclusions Our results suggest that the three-lncRNA signature is a new biomarker for the prognosis of patients with OSCC, enabling more accurate prediction of survival.

[1]  J. Rinn,et al.  Modular regulatory principles of large non-coding RNAs , 2012, Nature.

[2]  Jacques Ferlay,et al.  Estimates of cancer incidence in China for 2000 and projections for 2005. , 2005, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[3]  M. Toyota,et al.  Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors. , 2012, Cancer research.

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

[5]  J. Troge,et al.  Tumour evolution inferred by single-cell sequencing , 2011, Nature.

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

[7]  B. Rigas,et al.  Annexin 1 induced by anti-inflammatory drugs binds to NF-kappaB and inhibits its activation: anticancer effects in vitro and in vivo. , 2010, Cancer research.

[8]  Howard Y. Chang,et al.  Genome regulation by long noncoding RNAs. , 2012, Annual review of biochemistry.

[9]  N. Sharpless,et al.  Genetic "lnc"-age of noncoding RNAs to human disease. , 2012, The Journal of clinical investigation.

[10]  Andreas Ziegler,et al.  On safari to Random Jungle: a fast implementation of Random Forests for high-dimensional data , 2010, Bioinform..

[11]  F. Watt,et al.  Periplakin, a Novel Component of Cornified Envelopes and Desmosomes That Belongs to the Plakin Family and Forms Complexes with Envoplakin , 1997, The Journal of cell biology.

[12]  Shuhan Sun,et al.  Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans , 2011, Hepatology.

[13]  Ying Sun,et al.  Prognostic value of a microRNA signature in nasopharyngeal carcinoma: a microRNA expression analysis. , 2012, The Lancet. Oncology.

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

[15]  S. Haque Ethics approval This study was conducted with the approval of the East London and City Health Authority Ethic Committee. Provenance and peer review Not commissioned; externally peer reviewed. , 2011 .

[16]  Andreas Ziegler,et al.  On safari to Random Jungle: a fast implementation of Random Forests for high-dimensional data , 2010, Bioinform..

[17]  P. Fraser,et al.  No-Nonsense Functions for Long Noncoding RNAs , 2011, Cell.

[18]  Xiao-Hua Zhou,et al.  Multiple imputation: review of theory, implementation and software , 2007, Statistics in medicine.

[19]  E. Artifon,et al.  Competing interests: None , 2016 .

[20]  S. Miyano,et al.  Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. , 2011, Cancer research.

[21]  Jeremy J. W. Chen,et al.  A five-gene signature and clinical outcome in non-small-cell lung cancer. , 2007, The New England journal of medicine.

[22]  A. Jemal,et al.  Global cancer statistics , 2011, CA: a cancer journal for clinicians.

[23]  Joseph G Ibrahim,et al.  Missing data in clinical studies: issues and methods. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  Antoine M. van Oijen,et al.  Real-time single-molecule observation of rolling-circle DNA replication , 2009, Nucleic acids research.

[25]  Andrew H. Beck,et al.  Transcriptional profiling of long non-coding RNAs and novel transcribed regions across a diverse panel of archived human cancers , 2012, Genome Biology.

[26]  H. Spring,et al.  A novel cell-cell junction system: the cortex adhaerens mosaic of lens fiber cells , 2003, Journal of Cell Science.

[27]  Xin Ma,et al.  LncRNAs Expression Signatures of Renal Clear Cell Carcinoma Revealed by Microarray , 2012, PloS one.

[28]  Howard Y. Chang,et al.  Long noncoding RNA HOTAIR reprograms chromatin state to promote cancer metastasis , 2010, Nature.

[29]  J. Mattick,et al.  Genome-wide analysis of long noncoding RNA stability , 2012, Genome research.

[30]  Yang C. Yuan,et al.  Multiple Imputation for Missing Data: Concepts and New Development , 2000 .

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

[32]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[33]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

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

[35]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[36]  Howard Y. Chang,et al.  Long intergenic noncoding RNAs: new links in cancer progression. , 2011, Cancer research.

[37]  C. Kang,et al.  LncRNA profile of glioblastoma reveals the potential role of lncRNAs in contributing to glioblastoma pathogenesis. , 2012, International journal of oncology.

[38]  Brad T. Sherman,et al.  Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists , 2008, Nucleic acids research.