The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression

PLoS One. 2013 Oct 14;8(10):e77293. doi: 10.1371/journal.pone.0077293. eCollection 2013.

Abstract

HOTAIR, a long intervening non-coding RNA (lincRNA), associates with the Polycomb Repressive Complex 2 (PRC2) and is reported to reprogram chromatin organization and promote tumor progression. However, little is known about the roles of this gene in the development of chemoresistance phenotype of lung adenocarcinoma (LAD). Thus, we investigated the involvement of HOTAIR in the resistance of LAD cells to cisplatin. In this study, we show that HOTAIR expression was significantly upregulated in cisplatin-resistant A549/DDP cells compared with in parental A549 cells. Knockdown of HOTAIR by RNA interference could resensitize the responses of A549/DDP cells to cisplatin both in vitro and in vivo. In contrast, overexpression of HOTAIR could decrease the sensitivity of A549 and SPC-A1 cells to cisplatin. We also found that the siRNA/HOTAIR1-mediated chemosensivity enhancement was associated with inhibition of cell proliferation, induction of G0/G1 cell-cycle arrest and apoptosis enhancement through regulation of p21(WAF1/CIP1) (p21) expression. Also, pcDNA/p21or siRNA/p21 could mimic the effects of siRNA/HOTAIR1 or pcDNA/HOTAIR on the sensitivity of LAD cells to cisplatin. Importantly, siRNA/p21 or pcDNA/p21 could partially rescue the effects of siRNA/HOTAIR1 or pcDNA/HOTAIR on both p21 expression and cisplatin sensitivity in LAD cells. Further, HOTAIR was observed to be significantly downregulated in cisplatin-responding LAD tissues, and its expression was inversely correlated with p21 mRNA expression. Taken together, our findings suggest that upregulation of HOTAIR contributes to the cisplatin resistance of LAD cells, at least in part, through the regulation of p21 expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics*
  • Adenocarcinoma of Lung
  • Animals
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Cisplatin / therapeutic use*
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA, Complementary / genetics
  • Down-Regulation / drug effects
  • Down-Regulation / genetics*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Small Interfering / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / genetics

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA, Complementary
  • HOTAIR long untranslated RNA, human
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • Cisplatin

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (No.81272601), the Medical Key Talented Person Foundation of the Jiangsu Provincial Developing Health Project (No.RC2011080), Innovation Team Project of the Second Affiliated Hospital of Nanjing Medical University, the Jiangsu Provincial Personnel Department “the Great of Six Talented Man Peak” Project (No.09-B1-021) and “333 high class Talented Man Project” (No.2011-III-2630). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.