Abstract
Simple SummaryBarrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Long noncoding RNAs (lncRNAs) have been identified as key regulators of biological pathways and we identified lncRNA, miR205HG, as a tumor suppressor in the development of Barrett’s esophagus and esophageal adenocarcinoma, in part through its effect on the Hedgehog signaling pathway. The aims of the current study were: (1) to study involvement of miR205HG in the development of BE and EAC (2) to clarify the role of miR205HG in in vitro and in vivo experiments; and (3) to investigate the mechanism of miR205HG involving the Hedgehog (Hh) signaling pathwayBarrett’s esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Recently, long noncoding RNAs (lncRNAs) have been identified as key regulators of biological pathways. However, involvement of lncRNAs in the development of BE and EAC has not been well-studied. The aims of the current study were: (1) to study involvement of the lncRNA, miR205HG, in the development of BE and EAC; (2) to clarify the role of miR205HG in in vitro and in vivo experiments; and (3) to investigate the mechanism of miR205HG involving the Hedgehog (Hh) signaling pathway. These experiments revealed that miR205HG was downregulated in EAC vs. normal esophageal epithelia (NE) as well as in EAC cell lines, and its forced overexpression inhibited EAC cell proliferation and cell cycle progression in vitro. Similarly, overexpression of miR205HG inhibited xenograft tumor growth in mice In vivo. Finally, we show that one mechanism of action of miR205HG involves the Hh signaling pathway: miR205HG and Hh expression levels were inversely correlated in both EAC (r = −0.73) and BE (r = −0.83) tissues, and in vitro studies revealed details of Hh signaling inhibition induced by miR205HG. In conclusion, these findings establish that lncRNA miR205HG functions as a tumor suppressor in the development of BE and EAC, at least in part through its effect on the Hh signaling pathway.
Highlights
Esophageal adenocarcinoma (EAC) is the predominant histopathologic subtype of esophageal cancer in the United States and other Western countries [1]
To identify tumor suppressor long noncoding RNAs (lncRNAs) involved in Barrettogenesis and esophageal adenocarcinogenesis, we performed RNA-seq of two normal esophageal epithelia (NE)-Barrett’s esophagus (BE)-esophageal adenocarcinoma (EAC) matched tissue sets and two NE-BE matched tissue pairs
This RNA-seq analysis identified 1531 lncRNAs. Among these 1531 lncRNAs, we prioritized lncRNAs with highest expression in NE (NE normalized copy number ≥ 10) that were sequentially downregulated during the NE-BE-EAC progression continuum. This filtering process identified 11 lncRNAs (Table 2), among which CTA-55I10.1 had the highest NE/BE and NE/EAC fold changes of these 11 candidate lncRNAs. miR205HG is a microRNA-host gene, which harbors within its intron 3-exon 4 junction a miRNA-containing hairpin that serves as the template for two distinct miRNAs, miR-205 and miR-205* (Figure 1)
Summary
Esophageal adenocarcinoma (EAC) is the predominant histopathologic subtype of esophageal cancer in the United States and other Western countries [1]. EAC incidence has increased sevenfold over the past three decades, while that of other common cancers has declined [1,2]. Most EACs are detected at advanced stages, with five-year survival rates < 20% [3]. The rising incidence and poor prognosis of this cancer emphasize the need for understanding key etiologic factors. Barrett’s esophagus (BE) is the major predisposing factor to EAC [4]. A diagnosis of BE confers an 11- to 30-fold increase in EAC risk, while BE affects 1.6–6.8 percent of the general population [5]. It is crucial to improve our understanding of EAC’s underlying molecular mechanisms. A better understanding of the molecular basis of BE and EAC may yield earlier detection, more effective individualized cancer risk evaluation, and novel therapeutic approaches
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