期刊
CANCER BIOLOGY & MEDICINE
卷 19, 期 9, 页码 1385-1396出版社
CHINA ANTI-CANCER ASSOC
DOI: 10.20892/j.issn.2095-3941.2022.0068
关键词
Non-small cell lung cancer; chromosome 2q33.1; risk; caspase-8; apoptosis
资金
- National Natural Science Foundation of China [82103926, 81702266]
- Science Fund for Creative Research Groups of the National Natural Science Foundation of China [81521004]
- Natural Science Foundation of Jiangsu Province [BK20210534]
- Postdoctoral Science Foundation of China [2021M691636]
- CAMS Innovation Fund for Medical Sciences [2019RU038]
- Graduate Research and Innovation Program of Jiangsu Province [KYCX20_1442, KYCX20_1412]
This study identified the causal variant rs3769823 in chromosome 2q33.1 and explored its biological functions in non-small cell lung cancer (NSCLC). The variant was found to inhibit the proliferation and metastasis of lung cancer cells and was involved in the apoptosis pathway.
Objective: Although our previous genome-wide association study (GWAS) has identified chromosome 2q33.1 as a susceptibility locus for non-small cell lung cancer (NSCLC), the causal variants remain unclear. The aims of this study were to identify the causal variants in 2q33.1 and to explore their biological functions in NSCLC. Methods: CCK-8, colony formation, EdU incorporation, Transwell, and quantitative real-time polymerase chain reaction assays were applied to examine variant function. The tumor xenograft model was used to examine variant function in vivo. Caspase-8 activity assays, flow cytometry analysis, and co-immunoprecipitation assays were used to explore the molecular mechanism. Results: The missense variant rs3769823 (A > G), which caused the substitution of lysine with arginine at amino acid 14 in caspase-8 (caspase-8K14R), was identified as a potential causal candidate in 2q33.1. Compared with the wild type caspase-8 (caspase-8WT) group, the caspase-8K14R group had higher expression of caspase-8 and cleaved caspase-8. Caspase-8K14R inhibited the proliferation and metastasis of human lung cancer cell lines in vitro. Moreover, caspase-8K14R repressed lung cancer cell growth in vivo. Mechanistically, caspase-8K14R was more sensitive than caspase-8WT to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and showed higher binding of caspase-8 and FADD. Conclusions: These results suggested that rs3769823 is the causal variant in chromosome 2q33.1 and is involved in an apoptosis pathway, leading to a decreased risk of NSCLC.
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