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

Abstract

BACKGROUND:

Although 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.

RESULTS:

Employing 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.

CONCLUSIONS:

In 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.

• Authors: Shuang Qu, Zichen Jiao, Geng Lu, Bing Yao, Ting Wang, Weiwei Rong, Jiahan Xu, Ting Fan, Xinlei Sun, Rong Yang, Jun Wang, Yongzhong Yao, Guifang Xu, Xin Yan, Tao Wang, Hongwei Liang, Ke Zen
• Journal: Genome biology (Genome Biol) Vol. 22 Issue 1 Pg. 104 (04 13 2021) ISSN: 1474-760X [Electronic] England
• PMID: 33849634 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• Proto-Oncogene Proteins c-myc
• RNA, Long Noncoding
• RNA, Messenger
• Interferon-gamma

Topics

• Adenocarcinoma of Lung (genetics, metabolism, pathology)
• Alternative Splicing
• Animals
• Apoptosis (genetics)
• B7-H1 Antigen (chemistry, genetics)
• Cell Line, Tumor
• Cell Proliferation
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic
• Heterografts
• Humans
• Interferon-gamma (metabolism)
• Mice
• Models, Molecular
• Protein Binding
• Proto-Oncogene Proteins c-myc (genetics, metabolism)
• RNA, Long Noncoding (chemistry, genetics)
• RNA, Messenger
• Signal Transduction
• Structure-Activity Relationship