Hypothyroidism reduces the risk of lung cancer through oxidative stress response and the PI3K/Akt signaling pathway: An RNA-seq and Mendelian randomization study

Wei Liu; Fei-Hang Zhi; Shao-Yi Zheng; Hao-Shuai Yang; Xi-Jie Geng; Hong-He Luo; Yan-Fen Feng; Yi-Yan Lei

doi:10.1016/j.heliyon.2023.e22661

Hypothyroidism reduces the risk of lung cancer through oxidative stress response and the PI3K/Akt signaling pathway: An RNA-seq and Mendelian randomization study

Heliyon. 2023 Nov 22;9(12):e22661. doi: 10.1016/j.heliyon.2023.e22661. eCollection 2023 Dec.

Authors

Wei Liu¹, Fei-Hang Zhi¹, Shao-Yi Zheng¹, Hao-Shuai Yang¹, Xi-Jie Geng², Hong-He Luo¹, Yan-Fen Feng^{3

4}, Yi-Yan Lei¹

Affiliations

¹ Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
² Operating Room and Anesthesia Centre, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
³ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China.
⁴ Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China.

Abstract

Hypothyroidism has been suggested to play a role in tumor progression. However, the causal association between hypothyroidism and lung cancer remains unknow. To elucidate the potential association between hypothyroidism and lung cancer risk, we employ a Mendelian randomization (MR) approach. MR was performed to analyze pooled data from the International Lung Cancer Consortium (11,348 cases and 15,861 controls; European ancestry) to determine the causal relationship between hypothyroidism and lung cancer. We used 36, 83, and 14 single nucleotide polymorphisms as instrumental variables for hypothyroidism/myxoedema, hypothyroidism, and exercise, respectively. We further investigated the mechanisms involved in transcriptome analysis using data from The Cancer Genome Atlas and Genotype-Tissue Expression database. We conducted an initial validation of intermediary factor using a two-step MR analysis. Genetically predicted hypothyroidism was significantly related to the risk of overall lung cancer, specifically the risk of lung squamous cell cancer (LSCC) but not with the risk of lung adenocarcinoma (LUAD) as assessed using the inverse-variance weighted (IVM) method. A similar causal association was found between hypothyroidism/myxoedema and the risk of lung cancer, LSCC, and LUAD. Transcriptome analysis showed that genes associated with hypothyroidism, lung cancer, and LSCC were enriched in the PI3K/Akt signaling pathway and oxidative stress response. However, genes related to hypothyroidism and LUAD did not exhibit enrichment in these pathways. Hypothyroidism was significantly associated with strenuous sports or other exercises. Moreover, genetically predicted exercise was significantly related to the risk of overall lung cancer, and LSCC, but not LUAD. We detected no horizontal pleiotropy using the MR-PRESSO and MR Egger regression intercept. Hypothyroidism was causally associated with a lower risk of lung cancer, and these effects might be mediated by the oxidative stress response and the PI3K/Akt signaling pathway. Therefore, our study suggests that the potential factors and viable etiologies of hypothyroidism that contributed to lung cancer risk deserve further investigation.

Keywords: Hypothyroidism; Lung cancer; Mendelian randomization analysis; Oxidative stress; PI3K/Akt signaling; Transcriptome analysis.