Abstract
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.
Highlights
Esophageal squamous cell carcinoma (ESCC) is one of the more prevalent and lethal cancers worldwide.[1,2] In eastern Asia, ESCC is associated with high morbidity and mortality compared with Western countries.[1,2] To date, ESCC-related research has primarily focused on the deregulation of protein-coding genes (PCGs) and microRNAs to identify oncogenes and tumor suppressors, thereby missing long non-coding RNAs.[3,4] LncRNAs are an RNA species 4200 bp in length and expressed in a tissue-specific manner
LncRNAs were expressed at levels lower than PCGs (Figure 1a), with expression levels of 75% long non-coding RNA (lncRNA) being less than 10 RPKM (Figure 1b)
These differentially expressed lncRNAs made up 4.3% of all expressed lncRNAs and PCGs, of which lncRNA made up 41.2% of all differential lncRNAs (Figure 1d)
Summary
Esophageal squamous cell carcinoma (ESCC) is one of the more prevalent and lethal cancers worldwide.[1,2] In eastern Asia, ESCC is associated with high morbidity and mortality compared with Western countries.[1,2] To date, ESCC-related research has primarily focused on the deregulation of protein-coding genes (PCGs) and microRNAs to identify oncogenes and tumor suppressors, thereby missing long non-coding RNAs (lncRNAs).[3,4] LncRNAs are an RNA species 4200 bp in length and expressed in a tissue-specific manner. Several well-described examples have shown that lncRNAs have critical roles in cancer initiation and progression, and may mediate oncogenic or tumor suppressing effects, as well as comprise a new class of cancer therapeutic targets.[5,6,7]. Examples include the increased expression of HOTAIR in metastatic breast cancer,[5] oncogenicity and tumor-suppressive properties of H19 in different cancers,[6] ANRIL-induced epigenetic silencing of p15 in leukemia,[7] and the ability of MALAT1 to confer high metastatic potential in non-small cell lung cancer.[8] In contrast to these well-described examples, little is known about the functions of most lncRNAs in caner initiation and progression
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