The Long Noncoding RNA MEG3 Contributes to Cisplatin Resistance of Human Lung Adenocarcinoma

PLoS One. 2015 May 20;10(5):e0114586. doi: 10.1371/journal.pone.0114586. eCollection 2015.

Abstract

Long noncoding RNAs (lncRNAs) have been identified as oncogenes or tumor suppressors that are involved in tumorigenesis and chemotherapy drug resistance. Maternally expressed gene 3 (MEG3) is an imprinted gene located at 14q32 that encodes an lncRNA, and decreased MEG3 expression plays an important role in multiple cancers. However, its biological role in the development of the chemoresistance phenotype of human lung adenocarcinoma (LAD) is unknown. This study aimed to observe the expression of MEG3 in LAD and to evaluate its biological role and clinical significance in the resistance of LAD cells to cisplatin. MEG3 expression was markedly decreased in cisplatin-resistant A549/DDP cells compared with parental A549 cells as shown by an lncRNA microarray. MEG3 overexpression in A549/DDP cells increased their chemosensitivity to cisplatin both in vitro and in vivo by inhibiting cell proliferation and inducing apoptosis. By contrast, MEG3 knockdown in A549 cells decreased the chemosensitivity. Moreover, MEG3 was decreased in cisplatin-insensitive LAD tissues while p53 protein levels were decreased and Bcl-xl protein levels increased. Furthermore, patients with lower levels of MEG3 expression showed worse responses to cisplatin-based chemotherapy. These findings demonstrate that MEG3 is significantly downregulated in LAD and partially regulates the cisplatin resistance of LAD cells through the control of p53 and Bcl-xl expression. Thus, MEG3 may represent a new marker of poor response to cisplatin and could be a potential therapeutic target for LAD chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic
  • Cisplatin / pharmacology*
  • Drug Resistance, Neoplasm / genetics*
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • RNA, Long Noncoding / genetics*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • MEG3 non-coding RNA, human
  • RNA, Long Noncoding
  • RNA, Messenger
  • Cisplatin

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (No.81272601,81372397,81472198), the Key Clinical Medicine Technology Foundation of Jiangsu Province (No.BL2014096), 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 Scientific Research Foundation of Jiangsu Province Health Department(No.H201310),“333 high class Talented Man Project” (No.2011-III-2630) and the School key Fund of Nanjing Medical University (2013NJMU054). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.