Open AccessFat mass and obesity‐associated protein regulates arecoline‐exposed oral cancer immune response through programmed cell death‐ligand 1
Author(s) -
Li Xia,
Chen Wuya,
Gao Yijun,
Song Jing,
Gu Yangcong,
Zhang Jianming,
Cheng Xiufeng,
Ai Yilong
Publication year - 2022
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15332
Subject(s) - arecoline , areca , downregulation and upregulation , cancer research , cancer , cell growth , cell , immune system , medicine , biology , immunology , receptor , biochemistry , gene , nut , muscarinic acetylcholine receptor , structural engineering , engineering
The high prevalence of oral squamous cell carcinoma (OSCC) in South Asia is associated with habitual areca nut chewing. Arecoline, a primary active carcinogen within areca nut extract, is known to promote OSCC pathological development. Dysregulation of N6‐methyladenosine (m6A) modification has begun to emerge as a significant contributor to cancer development and progression. However, the biological effects and molecular mechanisms of m6A modification in arecoline‐promoted OSCC malignance remain elusive. We reveal that chronic arecoline exposure substantially induces upregulation of fat mass and obesity‐associated protein (FTO), MYC, and programmed cell death‐ligand 1 (PD‐L1) in OSCC cells. Moreover, upregulation of PD‐L1 is observed in OSCC cell lines and tissues and is associated with areca nut chewing in OSCC patients. We also demonstrate that arecoline‐induced FTO promotes the stability and expression levels of PD ‐ L1 transcripts through mediating m6A modification and MYC activity, respectively. PD‐L1 upregulation confers superior cell proliferation, migration, and resistance to T‐cell killing to OSCC cells. Blockage of PD‐L1 by administration of anti‐PD‐L1 antibody shrinks tumor size and improves mouse survival by elevating T‐cell‐mediated tumor cell killing. Therefore, targeting PD‐L1 might be a potential therapeutic strategy for treating PD‐L1‐positive OSCC patients, especially those with habitual areca nut chewing.