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Integrative Analyses of Transcriptome Sequencing Identify Novel Functional Lncrnas in Esophageal Squamous Cell Carcinoma

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Integrative Analyses of Transcriptome Sequencing Identify Novel Functional Lncrnas in Esophageal Squamous Cell Carcinoma UCLA UCLA Previously Published Works Title Integrative analyses of transcriptome sequencing identify novel functional lncRNAs in esophageal squamous cell carcinoma. Permalink https://escholarship.org/uc/item/1js6k3nf Journal Oncogenesis, 6(2) ISSN 2157-9024 Authors Li, C-Q Huang, G-W Wu, Z-Y et al. Publication Date 2017-02-13 DOI 10.1038/oncsis.2017.1 Peer reviewed eScholarship.org Powered by the California Digital Library University of California OPEN Citation: Oncogenesis (2017) 6, e297; doi:10.1038/oncsis.2017.1 www.nature.com/oncsis ORIGINAL ARTICLE Integrative analyses of transcriptome sequencing identify novel functional lncRNAs in esophageal squamous cell carcinoma C-Q Li1,2,10, G-W Huang1,10, Z-Y Wu3,10, Y-J Xu4, X-C Li2, Y-J Xue1, Y Zhu1, J-M Zhao1,2,MLi2, J Zhang2, J-Y Wu1, F Lei1, Q-Y Wang1,2,SLi4, C-P Zheng3,BAi2, Z-D Tang2, C-C Feng2, L-D Liao1, S-H Wang3, J-H Shen3, Y-J Liu2, X-F Bai2, J-Z He1, H-H Cao1, B-L Wu1, M-R Wang5, D-C Lin6, HP Koeffler6,7,8, L-D Wang9,XLi4, E-M Li1 and L-Y Xu1 Long non-coding RNAs (lncRNAs) have a critical role in cancer initiation and progression, and thus may mediate oncogenic or tumor suppressing effects, as well as be a new class of cancer therapeutic targets. We performed high-throughput sequencing of RNA (RNA-seq) to investigate the expression level of lncRNAs and protein-coding genes in 30 esophageal samples, comprised of 15 esophageal squamous cell carcinoma (ESCC) samples and their 15 paired non-tumor tissues. We further developed an integrative bioinformatics method, denoted URW-LPE, to identify key functional lncRNAs that regulate expression of downstream protein- coding genes in ESCC. A number of known onco-lncRNA and many putative novel ones were effectively identified by URW-LPE. Importantly, we identified lncRNA625 as a novel regulator of ESCC cell proliferation, invasion and migration. ESCC patients with high lncRNA625 expression had significantly shorter survival time than those with low expression. LncRNA625 also showed specific prognostic value for patients with metastatic ESCC. Finally, we identified E1A-binding protein p300 (EP300) as a downstream executor of lncRNA625-induced transcriptional responses. These findings establish a catalog of novel cancer-associated functional lncRNAs, which will promote our understanding of lncRNA-mediated regulation in this malignancy. Oncogenesis (2017) 6, e297; doi:10.1038/oncsis.2017.1; published online 13 February 2017 INTRODUCTION the functions of most lncRNAs in caner initiation and progression. Esophageal squamous cell carcinoma (ESCC) is one of the more For example, ESCCAL-1 was found to be an onco-lncRNA in prevalent and lethal cancers worldwide.1,2 In eastern Asia, ESCC is esophageal cancer development, and high expression of BC200 or associated with high morbidity and mortality compared with MALAT1 has been shown to be a novel predictive marker for ESCC – Western countries.1,2 To date, ESCC-related research has primarily patients who received radical resection.9 11 Overall, a handful of – focused on the deregulation of protein-coding genes (PCGs) and lncRNAs have documented roles in ESCC.4,9 17 microRNAs to identify oncogenes and tumor suppressors, thereby Next-generation transcriptome sequencing (RNA-seq) has pro- missing long non-coding RNAs (lncRNAs).3,4 LncRNAs are an RNA vided a method to delineate the entire set of transcriptional species 4200 bp in length and expressed in a tissue-specific aberrations in a disease, including lncRNAs and PCGs. For manner. Several well-described examples have shown that example, using RNA-seq to analyze prostate cancer tissues, the lncRNAs have critical roles in cancer initiation and progression, landscape of lncRNAs in prostate cancer has been recently defined and thus may mediate oncogenic or tumor suppressing effects, and notably includes prostate cancer functional lncRNAs, such as as well as comprise a new class of cancer therapeutic targets.5–7 PCA118 and SChLAP1.19 In the case of ESCC, Ma et al.20 has applied Examples include the increased expression of HOTAIR in transcriptome sequencing to ESCC tissues from three patients and metastatic breast cancer,5 oncogenicity and tumor-suppressive adjacent non-tumor tissues. However, because the existing properties of H19 in different cancers,6 ANRIL-induced epigenetic transcriptome sequencing for ESCC focuses on research of PCGs, silencing of p15 in leukemia,7 and the ability of MALAT1 to confer most of the functional lncRNAs in ESCC have yet to be identified. high metastatic potential in non-small cell lung cancer.8 In The functions of lncRNAs are closely associated with their contrast to these well-described examples, little is known about abundance of transcripts and downstream target PCGs directly 1The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China; 2School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, China; 3Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou, China; 4College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China; 5Cancer Institute/Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; 6Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, CA, USA; 7Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; 8National University Cancer Institute of Singapore, National University Health System and National University Hospital, Singapore, Singapore and 9Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China. Correspondence: Professor L-Y Xu, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, No. 22, Xinling Road, Shantou, Guangdong 515041, China. E-mail: [email protected] or Professor E-M Li, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, No. 22, Xinling Road, Shantou, Guangdong 515041, China. E-mail: [email protected] or Professor X Li, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. E-mail: [email protected] 10These authors contributed equally to this work. Received 8 September 2016; revised 17 December 2016; accepted 23 December 2016 Identification of novel functional lncRNAs C-Q Li et al 2 or indirectly regulated by them.21 LncRNA-induced transcriptional based on our RNA-seq analysis. MIR31HG,29 a tumor-suppressive dysregulation of target PCGs has become an effective strategy to lncRNA known to be downregulated in glioblastoma, showed identify key functional lncRNAs and several successful methods increased expression in ESCC, suggesting complex and context- have been developed.11,22,23 For example, a random walk strategy dependent functions of lncRNAs in different cancer types. has been used to search for candidate prostate cancer-related DLX6-AS1, LINC00162 and NPPA-AS1, which were reported to lncRNAs in the lncRNA-PCG bipartite network based on sample function in development, narcolepsy and modulation of blood correlation, and a lncRNA-PCG co-expression network has been pressure,30–32 showed differential expression between ESCC tissue constructed to predict the functions of lncRNAs.22 A limitation of samples and paired non-tumor tissues, suggesting their function these methods is the requirement for known cancer lncRNAs to in ESCC. serve as seeds. However, for many diseases such as ESCC, only a few known lncRNAs are available to be used as seeds, which Identification of functional lncRNAs in ESCC decreases the predictive power for a disease. In addition, methods based on known lncRNAs as seeds also tend to identify LncRNAs do not encode protein, but often either directly or indirectly regulate transcription, splicing and translation of neighborhood lncRNAs of well-studied cancer lncRNAs, and thus 3 lack ability to identify novel functional lncRNAs. downstream target PCGs. These reports prompted us to test the correlation between the expression of lncRNA and PCG to Here, we perform RNA-seq to investigate expression levels of fi fi lncRNAs and PCGs in 30 esophageal samples (15 paired ESCC and pinpoint key lncRNAs. We identi ed 4,554 pair signi cant non-tumor esophageal tissues). We further developed a method, co-expression relationships between 615 differential lncRNAs denoted URW-LPE (for Unsupervised Random Walk method and 2182 differential PCGs. We further constructed an extended with each dysregulated LncRNA/PCG as a seed and extended lncRNA-PCG co-expression network based on differentially expressed lncRNAs/PCGs (Figure 2a). Edges in the network were co-Expression relation as an edge), to identify novel potential constructed if two molecules were significantly co-expressed (FDR functional lncRNAs based on global lncRNA-PCG network o1.0e-7) or they had direct protein-protein or lncRNA-protein information. interaction relationship in the HPRD or NPInter databases (Materials and methods section). In the final network, 615 lncRNAs RESULTS and 2182 PCGs with 16 809 edges remained. As shown in Expression analysis of ESCC-related lncRNAs and coding genes Figure 2a, the upregulated nodes exceeded the downregulated nodes. Four hundred fifty (73.17%) lncRNAs and 1456 (66.72%) RNA-seq was performed on 30 esophageal samples (15 paired
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