Long Noncoding RNAs in the Pathogenesis of Barrett's Esophagus and Esophageal Carcinoma

Abstract

For many years, only a small fraction of the human genome was believed to regulate cell function and development. This protein-coding portion composed only 1% to 2% of 3 billion human DNA base pairs-the remaining sequence was classified as junk DNA. Subsequent research has revealed that most of the genome is transcribed into a broad array of noncoding RNAs, ranging in size from microRNA (20-23 nucleotides) to long noncoding RNA (lncRNA, more than 200 nucleotides). These noncoding RNA classes have been shown to use diverse molecular mechanisms to control gene expression and organ system development. As anticipated, alterations in this large control system can contribute to disease pathogenesis and carcinogenesis. We review the involvement of noncoding RNAs, lncRNAs in particular, in development of Barrett's esophagus and esophageal carcinoma.

Keywords: Barrett's Esophagus; Esophageal Carcinoma; lncRNAs.

Figure 1. Cell functions controlled by lncRNAs

A. snRNAs form part of a nuclear spliceosome, which precisely removes introns from heterogeneous RNA to yield mature mRNAs consisting only of exons. B. Telomerase comprises the TERT protein subunit and a noncoding telomerse RNA (TER), which provides the template for synthesis and extension of telomeres. C. The lncRNA LUNAR causes chromosomal looping, resulting in placement of a transcriptional activating complex named mediator to act as an enhancer near the promoter of the IGF1R gene. D. During imprinting, 1 allele of a gene (such as an inhibitory lncRNA) is silenced by DNA methylation, permitting expression of neighboring genes. The other allele has reduced or absent methylation, resulting in lncRNA expression and cis repression of neighboring genes. E. The FMR1 mRNA encodes the FMR1 protein; the 5′ untranslated region of the FMR1 mRNA binds an expanded CGG triplet sequences at the gene promoter. This DNA–RNA hybrid prevents transcription of the FMR1 gene, leading to fragile X mental retardation. F. In response to DNA damage, cell levels of the lncRNA DINO greatly increase. DINO binds to and stabilizes TP53, allowing TP53 to regulate hundreds of gene targets.