Hyper-methylation and DNMT3A mediated LTC4S downregulation promoted lung adenocarcinoma tumorigenesis via mTORC1 signaling pathway

Yang Ren; Peng Zhang; Liqun Li; Mei Wang; Huiliang Hu; Yidan Shen; Ping Xu; Qingguo Wu; Feng Li

Heliyon (Jul 2024)

Hyper-methylation and DNMT3A mediated LTC4S downregulation promoted lung adenocarcinoma tumorigenesis via mTORC1 signaling pathway

Yang Ren,
Peng Zhang,
Liqun Li,
Mei Wang,
Huiliang Hu,
Yidan Shen,
Ping Xu,
Qingguo Wu,
Feng Li

Affiliations

Yang Ren: Department of Respiratory Disease and Critical Care Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
Peng Zhang: Department of Respiratory Disease and Critical Care Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
Liqun Li: Department of Respiratory Disease and Critical Care Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
Mei Wang: Department of Respiratory Disease and Critical Care Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
Huiliang Hu: Department of Respiratory Disease and Critical Care Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
Yidan Shen: Department of Respiratory Disease and Critical Care Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
Ping Xu: Department of Respiratory Disease and Critical Care Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
Qingguo Wu: Department of Respiratory Disease and Critical Care Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China; Corresponding author.
Feng Li: Department of Respiratory Disease and Critical Care Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China; Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, 200032, China; Corresponding author. Department of Respiratory Disease and Critical Care Medicine, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.

Journal volume & issue: Vol. 10, no. 13
p. e33203

Abstract

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Background: Lung adenocarcinoma is a malignancy characterized by high mortality rates and unfavorable prognosis. However, the role of Leukotriene C4 Synthase (LTC4S) in lung cancer remains uninvestigated. Methods: The expression and prognostic value of LTC4S in LUAD were analyzed using the GEPIA online database. Subsequently, the function of LTC4S in lung cancer cells was examined through gain-of function experiments, using assays to evaluate tumor malignant behavior. Subcutaneous xenograft experiments in vivo was used for investigating the functions of LTC4S. Then, tumor hallmark pathways were analyzed by GSEA. Western blot assay was used to validate the impact of LTC4S on mTORC1 pathway. Finally, the correlation of mRNA and methylation of LTC4S were analyzed by cBioPortal. qRT-PCR, ChIP-qPCR and ChIP-Atlas were used to verify the regulation factors of LTC4S low expression in LUAD cells. Results: LTC4S presented significant decreased expression and favorable prognostic significance in LUAD. LTC4S was correlated with clinical stages in LUAD, which showed decreased expression gradually and significantly along with TNM stages. LTC4S-co-expressed genes were closely related to Ras signaling pathway, and MAPK signaling pathway. Overexpression of LTC4S inhibited cancer malignant phenotype and tumor growth in vitro and vivo. GSEA analysis and Western blot assay suggested low expression of LTC4S activated mTORC1 signaling pathway in LUAD. Moreover, the DNA methylation level of LTC4S in LUAD tissue was markedly elevated compared to normal tissue. The hypermethylation of the LTC4S promoter by DNMT3A leads to the decreased expression of LTC4S in LUAD. Conclusions: In conclusion, low expression of LTC4S serves as an unfavorable prognostic marker and the critical function of LTC4S in controlling the progression of LUAD. This highlights the promise for exploring the clinical benefits of manipulating LTC4S in LUAD targeted therapies.

Published in Heliyon

ISSN: 2405-8440 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Science: Science (General); Social Sciences: Social sciences (General)
Website: https://www.cell.com/heliyon/home

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