Long non-coding RNA SSTR5-AS1 facilitates gemcitabine resistance via stabilizing NONO in gallbladder carcinoma

Biochem Biophys Res Commun. 2020 Feb 19;522(4):952-959. doi: 10.1016/j.bbrc.2019.10.104. Epub 2019 Dec 4.

Abstract

Gallbladder carcinoma (GBC) is the most aggressive carcinoma of the biliary tract, effective chemotherapy was critical for the patients with unresectable GBC. However, chemotherapy resistance is still problematic for clinicians. Here, we identified a specific long non-coding RNA, SSTR5-AS1, in GBC patient that facilitates gemcitabine resistance. SSTR5-AS1 is significantly increased in GBC samples and cell lines, especially in gemcitabine-resistant cell lines, and higher SSTR5-AS1 expression was correlated with poorer overall survival rate in GBC patients. Our data revealed that upregulated SSTR5-AS1 facilitates gemcitabine resistance via inhibiting apoptosis. Knockdown of SSTR5-AS1 sensitized drug resistant GBC cells to gemcitabine in vitro and strongly inhibited xenografts formed by drug resistant GBC cells in vivo. Moreover, we found via streptavidin pull down assay that NONO specifically binds to sense sequence of SSTR5-AS1 and prevented proteasome mediated NONO degradation, which resulted in increased NONO protein level without affecting the transcription of NONO. NONO functions as the downstream effector of SSTR5-AS1 and is required for SSTR5-AS1 mediated gemcitabine resistance. Collectively, our data provided novel insights into lncRNA-mediated chemotherapy resistance and suggested a novel therapeutic target to improve chemotherapy strategies for unresectable GBC patients.

Keywords: Chemotherapy resistance; Gallbladder carcinoma; Gemcitabine; NONO; SSTR5-AS1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism*
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Gallbladder Neoplasms / genetics*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Mice, Nude
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Stability / drug effects
  • Proteolysis / drug effects
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA-Binding Proteins / metabolism*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • DNA-Binding Proteins
  • NONO protein, human
  • RNA, Long Noncoding
  • RNA-Binding Proteins
  • Deoxycytidine
  • gemcitabine
  • Proteasome Endopeptidase Complex