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Depiction of Aging-Based Molecular Phenotypes With Diverse Clinical Prognosis and Immunological Features in Gastric Cancer

OBJECTIVE: Aging acts as a dominating risk factor for human cancers. Herein, we systematically dissected the features of transcriptional aging-relevant genes in gastric cancer from multiple perspectives. METHODS: Based on the transcriptome profiling of prognostic aging-relevant genes, patients with...

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Autores principales: He, Fang, Ding, Huan, Zhou, Yang, Wang, Yuanzhen, Xie, Juan, Yang, Shaoqi, Zhu, Yongzhao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8843835/
https://www.ncbi.nlm.nih.gov/pubmed/35178409
http://dx.doi.org/10.3389/fmed.2021.792740
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author He, Fang
Ding, Huan
Zhou, Yang
Wang, Yuanzhen
Xie, Juan
Yang, Shaoqi
Zhu, Yongzhao
author_facet He, Fang
Ding, Huan
Zhou, Yang
Wang, Yuanzhen
Xie, Juan
Yang, Shaoqi
Zhu, Yongzhao
author_sort He, Fang
collection PubMed
description OBJECTIVE: Aging acts as a dominating risk factor for human cancers. Herein, we systematically dissected the features of transcriptional aging-relevant genes in gastric cancer from multiple perspectives. METHODS: Based on the transcriptome profiling of prognostic aging-relevant genes, patients with gastric cancer in The Cancer Genome Atlas (TCGA) stomach adenocarcinoma (TCGA-STAD) cohort were clustered with a consensus clustering algorithm. Mutational landscape and chemotherapeutic responses were analyzed and immunological features (immunomodulators, immune checkpoint molecules, cancer immunity cycle, and tumor-infiltrating immune cells) were systematically evaluated across gastric cancer. Weighted gene co-expression network (WGCNA) was conducted for screening aging molecular phenotype-relevant genes, and key genes were identified with Molecular Complex Detection (MCODE) analyses. Expressions of key genes were examined in 20 paired tumors and controls with RT-qPCR and Western blotting. Proliferation and apoptosis were investigated in two gastric cancer cells under MYL9 deficiency. RESULTS: Three aging-based molecular phenotypes (namely, C1, C2, and C3) were conducted in gastric cancer. Phenotype C1 presented the most prominent survival advantage and highest mutational frequencies. Phenotype C2 indicated low responses to sorafenib and gefitinib, while C3 indicated low responses to vinorelbine and gemcitabine. Additionally, phenotype C2 was characterized by enhanced immune and stromal activation and an inflamed tumor microenvironment. Seven aging molecular phenotype-relevant key genes (ACTA2, CALD1, LMOD1, MYH11, MYL9, MYLK, and TAGLN) were identified, which were specifically upregulated in tumors and in relation to dismal prognosis. Among them, MYL9 deficiency reduced proliferation and enhanced apoptosis in gastric cancer cells. CONCLUSION: Collectively, aging-based molecular subtypes may offer more individualized therapy recommendations and prognosis assessment for patients in distinct subtypes.
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spelling pubmed-88438352022-02-16 Depiction of Aging-Based Molecular Phenotypes With Diverse Clinical Prognosis and Immunological Features in Gastric Cancer He, Fang Ding, Huan Zhou, Yang Wang, Yuanzhen Xie, Juan Yang, Shaoqi Zhu, Yongzhao Front Med (Lausanne) Medicine OBJECTIVE: Aging acts as a dominating risk factor for human cancers. Herein, we systematically dissected the features of transcriptional aging-relevant genes in gastric cancer from multiple perspectives. METHODS: Based on the transcriptome profiling of prognostic aging-relevant genes, patients with gastric cancer in The Cancer Genome Atlas (TCGA) stomach adenocarcinoma (TCGA-STAD) cohort were clustered with a consensus clustering algorithm. Mutational landscape and chemotherapeutic responses were analyzed and immunological features (immunomodulators, immune checkpoint molecules, cancer immunity cycle, and tumor-infiltrating immune cells) were systematically evaluated across gastric cancer. Weighted gene co-expression network (WGCNA) was conducted for screening aging molecular phenotype-relevant genes, and key genes were identified with Molecular Complex Detection (MCODE) analyses. Expressions of key genes were examined in 20 paired tumors and controls with RT-qPCR and Western blotting. Proliferation and apoptosis were investigated in two gastric cancer cells under MYL9 deficiency. RESULTS: Three aging-based molecular phenotypes (namely, C1, C2, and C3) were conducted in gastric cancer. Phenotype C1 presented the most prominent survival advantage and highest mutational frequencies. Phenotype C2 indicated low responses to sorafenib and gefitinib, while C3 indicated low responses to vinorelbine and gemcitabine. Additionally, phenotype C2 was characterized by enhanced immune and stromal activation and an inflamed tumor microenvironment. Seven aging molecular phenotype-relevant key genes (ACTA2, CALD1, LMOD1, MYH11, MYL9, MYLK, and TAGLN) were identified, which were specifically upregulated in tumors and in relation to dismal prognosis. Among them, MYL9 deficiency reduced proliferation and enhanced apoptosis in gastric cancer cells. CONCLUSION: Collectively, aging-based molecular subtypes may offer more individualized therapy recommendations and prognosis assessment for patients in distinct subtypes. Frontiers Media S.A. 2022-02-01 /pmc/articles/PMC8843835/ /pubmed/35178409 http://dx.doi.org/10.3389/fmed.2021.792740 Text en Copyright © 2022 He, Ding, Zhou, Wang, Xie, Yang and Zhu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
He, Fang
Ding, Huan
Zhou, Yang
Wang, Yuanzhen
Xie, Juan
Yang, Shaoqi
Zhu, Yongzhao
Depiction of Aging-Based Molecular Phenotypes With Diverse Clinical Prognosis and Immunological Features in Gastric Cancer
title Depiction of Aging-Based Molecular Phenotypes With Diverse Clinical Prognosis and Immunological Features in Gastric Cancer
title_full Depiction of Aging-Based Molecular Phenotypes With Diverse Clinical Prognosis and Immunological Features in Gastric Cancer
title_fullStr Depiction of Aging-Based Molecular Phenotypes With Diverse Clinical Prognosis and Immunological Features in Gastric Cancer
title_full_unstemmed Depiction of Aging-Based Molecular Phenotypes With Diverse Clinical Prognosis and Immunological Features in Gastric Cancer
title_short Depiction of Aging-Based Molecular Phenotypes With Diverse Clinical Prognosis and Immunological Features in Gastric Cancer
title_sort depiction of aging-based molecular phenotypes with diverse clinical prognosis and immunological features in gastric cancer
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8843835/
https://www.ncbi.nlm.nih.gov/pubmed/35178409
http://dx.doi.org/10.3389/fmed.2021.792740
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