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PD-L1 lncRNA splice isoform promotes lung adenocarcinoma progression via enhancing c-Myc activity

Authors
  • Qu, Shuang1, 2
  • Jiao, Zichen3
  • Lu, Geng1
  • Yao, Bing4
  • Wang, Ting1
  • Rong, Weiwei1
  • Xu, Jiahan1
  • Fan, Ting1
  • Sun, Xinlei1
  • Yang, Rong1
  • Wang, Jun1
  • Yao, Yongzhong1
  • Xu, Guifang1
  • Yan, Xin1
  • Wang, Tao3
  • Liang, Hongwei1, 2
  • Zen, Ke1
  • 1 Nanjing University, Nanjing, China , Nanjing (China)
  • 2 China Pharmaceutical University, Nanjing, China , Nanjing (China)
  • 3 Department of Thoracic Surgery, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China , Nanjing (China)
  • 4 Nanjing Medical University, Nanjing, China , Nanjing (China)
Type
Published Article
Publication Date
Apr 13, 2021
Volume
22
Issue
1
Identifiers
DOI: 10.1186/s13059-021-02331-0
Source
Springer Nature
License
Green

Abstract

BackgroundAlthough using a blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism and efficacy of such immune-checkpoint inhibition strategies in solid tumors remains unclear.ResultsEmploying qRT-PCR, Sanger sequencing, and RNA BaseScope analysis, we show that human lung adenocarcinoma (LUAD) all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) by alternative splicing, regardless if the tumor is positive or negative for the protein PD-L1. Similar to PD-L1 mRNA, PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc promotes lung adenocarcinoma progression through directly binding to c-Myc and enhancing c-Myc transcriptional activity.ConclusionsIn summary, the PD-L1 gene can generate a long non-coding RNA through alternative splicing to promote lung adenocarcinoma progression by enhancing c-Myc activity. Our results argue in favor of investigating PD-L1-lnc depletion in combination with PD-L1 blockade in lung cancer therapy.

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