Long non-coding RNAHNF1A-AS1regulates proliferation and migration in oesophageal adenocarcinoma cells

Abstract

Objectives Long non-coding RNAs (IncRNA) have been shown to play important roles in the development and progression of cancer. However, functional IncRNAs and their downstream mechanisms are largely unknown in the molecular pathogenesis of oesophageal adenocarcinoma (EAC) and its progression. Design IncRNAs that are abnormally upregulated in EACs were identified by RNA-sequencing analysis, followed by quantitative RT-PCR (qRTPCR) validation using tissues from 25 EAC patients. Cell biological assays in combination with small interfering RNA-mediated knockdown were performed in order to probe the functional relevance of these IncRNAs. Results We discovered that a IncRNA, HNF1A-AS1, is markedly upregulated in human primary EACs relative to their corresponding normal oesophageal tissues (mean fold change 10.6, p<0.01). We further discovered that HNF1A-AS1 knockdown significantly inhibited cell proliferation and anchorage-independent growth, suppressed S-phase entry, and inhibited cell migration and invasion in multiple in vitro EAC models (p<0.05). A gene ontological analysis revealed that HNF1A-AS1 knockdown preferentially affected genes that are linked to assembly of chromatin and the nucleosome, a mechanism essential to cell cycle progression. The well known cancer-related IncRNA, H19, was the gene most markedly inhibited by HNF1A-AS1 knockdown. Consistent to this finding, there was a significant positive correlation between HNF1A-AS1 and H19 expression in primary EACs (p<0.01). Conclusions We have discovered abnormal upregulation of a IncRNA, HNF1A-AS1, in human EAC. Our findings suggest that dysregulation of HNF1A-AS1 participates in oesophageal tumorigenesis, and that this participation may be mediated, at least in part, by modulation of chromatin and nucleosome assembly as well as by H19 induction.

Novel Aberrations Uncovered in Barrett's Esophagus and Esophageal Adenocarcinoma Using Whole Transcriptome Sequencing

“…Therefore, we sought to systematically characterize lncRNA dysregulation at different stages of Barrett's disease. Previously, only two lncRNAs (HNF1A-AS1 and AFAP-AS1) have been reported as upregulated in EAC (16,17). Although these were upregulated in EAC compared with NE, we observed no difference between EAC and NDBE/LGD (Supplementary Fig.…”

“…Most microarray-based transcriptome analyses will for example miss a large proportion of long noncoding RNAs (lncRNAs), which are involved in almost all known cellular processes (10)(11)(12)(13)(14), and are important in cancer biology, as shown by the number of functional characterized lncRNAs involved in carcinogenesis (15). In EAC, only two lncRNAs have been reported (16,17), and no systematic approach identifying lncRNAs dysregulation at different stages of Barrett's disease and EAC development has been published so far.…”

lncRNA uc009yby.1 promotes renal cell proliferation and is associated with poor survival in patients with clear cell renal cell carcinomas

“…Furthermore, the function of uc009yby.1 in renal cells was investigated using two siRNAs to inhibit uc009yby.1 expression, revealing that this lncRNA could enhance renal cell proliferation; this suggests that uc009yby.1 may be a novel therapeutic target for ccRCC. Numerous studies have indicated that certain lncRNAs have aberrant expression profiles in various kinds of tumors, such as gastric (15)(16)(17), colon (18,19), esophageal (20)(21)(22) and liver (23) cancers. Yu et al (12) recently reported on a class of lncRNAs that are aberrantly expressed in ccRCC cells, in which multiple lncRNAs were upregulated.…”

Long Noncoding RNA in Digestive Tract Cancers: Function, Mechanism, and Potential Biomarker

“…They further confirmed that HNF1A, the sense-cognate gene for HNF1A-AS1, was not an HNF1A-AS1 target. Mechanistic investigation via gene ontology enrichment analysis revealed that HNF1A-AS1 knockdown dysregulated the expression of genes involved in cell cycle regulation and affected the expression of a cancer-related lncRNA H19, suggesting that one lncRNA may influence the function of another lncRNA in EACs [47].…”