Dongdong Wang, Mingwei Zhan, Pengfei Liu, Yi Yu, Rijian Guan
{"title":"Integrative Mendelian Randomization and Transcriptome Analysis Unveil Dual Pathways in Prostate Cancer Etiology","authors":"Dongdong Wang, Mingwei Zhan, Pengfei Liu, Yi Yu, Rijian Guan","doi":"10.1155/ijcp/9943789","DOIUrl":null,"url":null,"abstract":"<div>\n <p><b>Background:</b> Prostate cancer remains a significant global health challenge, influenced by both genetic and environmental factors. Despite extensive research, the specific metabolic pathways contributing to its pathogenesis are not fully understood.</p>\n <p><b>Methods:</b> We obtained significant single nucleotide polymorphisms (SNPs) associated with 1400 metabolites and 731 immune cells from the GEWAS database and published literature. Using an integrative approach that combines single-cell and bulk transcriptome analysis with Mendelian randomization (MR) and machine learning, we identified significant SNPs related to metabolic and immune profiles, with a specific focus on glutathione metabolism and its downstream metabolite cysteinylglycine disulfide. Advanced statistical techniques, including inverse variance weighted MR, were employed to explore causal relationships between these metabolic markers and prostate cancer risk. Additionally, we investigated the role of ATP6V1G1 in prostate cancer cell lines through RNA interference and various functional assays.</p>\n <p><b>Results:</b> Our MR analysis indicated that elevated cysteinylglycine disulfide levels are protective against prostate cancer. Conversely, higher monocyte counts were associated with increased cancer risk, suggesting a dual pathway influence on disease etiology through immune modulation and metabolic dysregulation. Machine learning algorithms further validated these associations and identified potential biomarkers for prostate cancer susceptibility. In vitro experiments demonstrated that silencing ATP6V1G1 significantly reduced the proliferation and migration of prostate cancer cells, highlighting its oncogenic potential.</p>\n <p><b>Conclusion:</b> The study highlighted a significant association between prostate cancer occurrence, glutathione metabolism, and monocyte activity. The critical interplay between glutathione metabolism and immune cell dynamics in prostate cancer is underscored, proposing novel biomarkers for early diagnosis and potential therapeutic targets. Notably, ATP6V1G1 emerged as a key gene with significant diagnostic and prognostic value, offering new prospects for therapeutic intervention in prostate cancer.</p>\n </div>","PeriodicalId":13782,"journal":{"name":"International Journal of Clinical Practice","volume":"2025 1","pages":""},"PeriodicalIF":2.2000,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/ijcp/9943789","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Clinical Practice","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1155/ijcp/9943789","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"MEDICINE, GENERAL & INTERNAL","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Prostate cancer remains a significant global health challenge, influenced by both genetic and environmental factors. Despite extensive research, the specific metabolic pathways contributing to its pathogenesis are not fully understood.
Methods: We obtained significant single nucleotide polymorphisms (SNPs) associated with 1400 metabolites and 731 immune cells from the GEWAS database and published literature. Using an integrative approach that combines single-cell and bulk transcriptome analysis with Mendelian randomization (MR) and machine learning, we identified significant SNPs related to metabolic and immune profiles, with a specific focus on glutathione metabolism and its downstream metabolite cysteinylglycine disulfide. Advanced statistical techniques, including inverse variance weighted MR, were employed to explore causal relationships between these metabolic markers and prostate cancer risk. Additionally, we investigated the role of ATP6V1G1 in prostate cancer cell lines through RNA interference and various functional assays.
Results: Our MR analysis indicated that elevated cysteinylglycine disulfide levels are protective against prostate cancer. Conversely, higher monocyte counts were associated with increased cancer risk, suggesting a dual pathway influence on disease etiology through immune modulation and metabolic dysregulation. Machine learning algorithms further validated these associations and identified potential biomarkers for prostate cancer susceptibility. In vitro experiments demonstrated that silencing ATP6V1G1 significantly reduced the proliferation and migration of prostate cancer cells, highlighting its oncogenic potential.
Conclusion: The study highlighted a significant association between prostate cancer occurrence, glutathione metabolism, and monocyte activity. The critical interplay between glutathione metabolism and immune cell dynamics in prostate cancer is underscored, proposing novel biomarkers for early diagnosis and potential therapeutic targets. Notably, ATP6V1G1 emerged as a key gene with significant diagnostic and prognostic value, offering new prospects for therapeutic intervention in prostate cancer.
期刊介绍：
IJCP is a general medical journal. IJCP gives special priority to work that has international appeal.
IJCP publishes:
Editorials. IJCP Editorials are commissioned. [Peer reviewed at the editor''s discretion]
Perspectives. Most IJCP Perspectives are commissioned. Example. [Peer reviewed at the editor''s discretion]
Study design and interpretation. Example. [Always peer reviewed]
Original data from clinical investigations. In particular: Primary research papers from RCTs, observational studies, epidemiological studies; pre-specified sub-analyses; pooled analyses. [Always peer reviewed]
Meta-analyses. [Always peer reviewed]
Systematic reviews. From October 2009, special priority will be given to systematic reviews. [Always peer reviewed]
Non-systematic/narrative reviews. From October 2009, reviews that are not systematic will be considered only if they include a discrete Methods section that must explicitly describe the authors'' approach. Special priority will, however, be given to systematic reviews. [Always peer reviewed]
''How to…'' papers. Example. [Always peer reviewed]
Consensus statements. [Always peer reviewed] Short reports. [Always peer reviewed]
Letters. [Peer reviewed at the editor''s discretion]
International scope
IJCP publishes work from investigators globally. Around 30% of IJCP articles list an author from the UK. Around 30% of IJCP articles list an author from the USA or Canada. Around 45% of IJCP articles list an author from a European country that is not the UK. Around 15% of articles published in IJCP list an author from a country in the Asia-Pacific region.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
