A novel long non-coding RNA lnc-GNAT1-1 is low expressed in colorectal cancer and acts as a tumor suppressor through regulating RKIP-NF-κB-Snail circuit

J Exp Clin Cancer Res. 2016 Dec 3;35(1):187. doi: 10.1186/s13046-016-0467-z.

Abstract

Background: The role of long non-coding RNAs (lncRNAs) in colorectal cancer (CRC) progression has not fully been elucidated. This study was designed to report the identification of a novel lncRNA, lnc-GNAT1-1, and its functional role in CRC progression.

Methods: lncRNA expression profile microarray was performed in three paired primary and liver metastatic tissues of CRC, and a novel lncRNA, lnc-GNAT1-1, was identified to be a potential functional lncRNA. Quantitative real-time PCR was used to detect its expression in CRC tissues, cell lines, and patients' plasma, cell fractionation was used to evaluate its subcellular location. lnc-GNAT1-1 was knockdown by siRNA or overexpressed by a lentivirus vector, then in vitro an vivo experiments were performed to evaluate its biological role and the underlying mechanisms in CRC.

Results: Expression of lnc-GNAT1-1 was decreased in liver metastasis than the primary tumor, while the later one is lower than the paired normal mucosa. Decreased lnc-GNAT1-1 expression was associated unfavorable clinicopathological features and a poor prognosis of CRC patients. In multivariate analysis, lnc-GNAT1-1 was proved to be an independent prognostic factor. In plasma, lnc-GNAT1-1 was significant decreased in CRC patients than healthy donors, and with the TNM stages advanced, the plasma lnc-GNAT1-1 level decreased; Receiver operating characteristic curve (ROC curve) showed that plasma lnc-GNAT1-1 had a moderate to well diagnostic efficiency for CRC. In vitro experiments showed that knockdown of lnc-GNAT1-1 could inhibit the aggressive phenotypes of CRC cell lines. In vivo study showed that overexpression of lnc-GNAT1-1 could suppress the liver metastasis of CRC cells. Finally, we explored the underlying mechanism of the role lnc-GNAT1-1 plays in CRC, and found a positive correlation between lnc-GNAT1-1 and Raf kinase inhibitor protein (RKIP) expression both in cells and in patients' tissues. We further found that lnc-GNAT1-1 could regulate the RKIP-NF-κB-Snail circuit in CRC.

Conclusions: We have demonstrated in this study that a novel lncRNA, lnc-GNAT1-1, is low expressed in colorectal cancer tissues and plasma, and acts as a tumor suppressor through regulating RKIP-NF-κB-Snail circuit.

Keywords: Long non-coding RNA; NF-κB; RKIP; Snail; lnc-GNAT1-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colorectal Neoplasms / blood
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Down-Regulation*
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Liver Neoplasms / blood
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / secondary*
  • Male
  • Mice
  • NF-kappa B / genetics
  • Neoplasm Staging
  • Neoplasm Transplantation
  • Oligonucleotide Array Sequence Analysis / methods
  • Phosphatidylethanolamine Binding Protein / genetics
  • Prognosis
  • RNA, Long Noncoding / blood
  • RNA, Long Noncoding / genetics*
  • Signal Transduction
  • Snail Family Transcription Factors / genetics

Substances

  • NF-kappa B
  • PEBP1 protein, human
  • Phosphatidylethanolamine Binding Protein
  • RNA, Long Noncoding
  • Snail Family Transcription Factors
  • long non-coding RNA GNAT1-1, human