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Original Article | Open Access

A causal variant rs3769823 in 2q33.1 involved in apoptosis pathway leading to a decreased risk of non-small cell lung cancer

Xu Zhang1,*, Na Qin1,2,*, Jingyi Fan3, Chang Zhang1, Qi Sun1, Yayun Gu1,2, Meng Zhu1,2, Erbao Zhang1,2, Juncheng Dai1,2, Guangfu Jin1,2, Hongxia Ma1,2,4, Zhibin Hu1,2, Hongbing Shen1,2,4 ( )
Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China
Health Management Center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou 215008, China
Research Units of Cohort Study on Cardiovascular Diseases and Cancers, Chinese Academy of Medical Sciences, Beijing 100730, China

*These authors contributed equally to this work.

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Abstract

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.

Keywords

riskapoptosisNon-small cell lung cancercaspase-8chromosome 2q33.1

Electronic Supplementary Material

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Cancer Biology & Medicine
Volume 19 Issue 9,
September 2022
Pages 1385-1396
DOI: 10.20892/j.issn.2095-3941.2022.0068
Cite this article:
Zhang X, Qin N, Fan J, et al. A causal variant rs3769823 in 2q33.1 involved in apoptosis pathway leading to a decreased risk of non-small cell lung cancer. Cancer Biology & Medicine, 2022, 19(9): 1385-1396. https://doi.org/10.20892/j.issn.2095-3941.2022.0068

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Received: 14 February 2022
Accepted: 15 June 2022
Published: 22 September 2022
©2022 Cancer Biology & Medicine.

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