Identification of NSP3 (SH2D3C) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from Allium sativum L. as Therapeutic Candidates

The multi-domain non-structural protein 3 (NSP3) is an oncogenic molecule that has been concomitantly implicated in the progression of coronavirus infection. However, its oncological role in lung cancer and whether it plays a role in modulating the tumor immune microenvironment is...

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Autores principales:	Yuan-Chieh Yeh, Bashir Lawal, Michael Hsiao, Tse-Hung Huang, Chi-Ying F. Huang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>NSP3 (SH2D3C)</i> NSCLC tumor microenvironment immune infiltrations dysfunctional T-cell phenotypes in silico study Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c7fcc56987a24b0b9f044b50734d6b57
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spelling	oai:doaj.org-article:c7fcc56987a24b0b9f044b50734d6b572021-11-25T16:49:17ZIdentification of <i>NSP3</i> (<i>SH2D3C</i>) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from <i>Allium sativum</i> L. as Therapeutic Candidates10.3390/biomedicines91115822227-9059https://doaj.org/article/c7fcc56987a24b0b9f044b50734d6b572021-10-01T00:00:00Zhttps://www.mdpi.com/2227-9059/9/11/1582https://doaj.org/toc/2227-9059The multi-domain non-structural protein 3 (<i>NSP3</i>) is an oncogenic molecule that has been concomitantly implicated in the progression of coronavirus infection. However, its oncological role in lung cancer and whether it plays a role in modulating the tumor immune microenvironment is not properly understood. In the present in silico study, we demonstrated that <i>NSP3 (SH2D3C)</i> is associated with advanced stage and poor prognoses of lung cancer cohorts. Genetic alterations of <i>NSP3 (SH2D3C</i>) co-occurred inversely with Epidermal Growth Factor Receptor (<i>EGFR</i>) alterations and elicited its pathological role via modulation of various components of the immune and inflammatory pathways in lung cancer. Our correlation analysis suggested that <i>NSP3 (SH2D3C)</i> promotes tumor immune evasion via dysfunctional T-cell phenotypes and T-cell exclusion mechanisms in lung cancer patients. <i>NSP3 (SH2D3C)</i> demonstrated a high predictive value and association with therapy resistance in lung cancer, hence serving as an attractive target for therapy exploration. We evaluated the in silico drug-likeness and <i>NSP3 (SH2D3C)</i> target efficacy of six organosulfur small molecules from <i>Allium sativum</i> using a molecular docking study. We found that the six organosulfur compounds demonstrated selective cytotoxic potential against cancer cell lines and good predictions for ADMET properties, drug-likeness, and safety profile. E-ajoene, alliin, diallyl sulfide, 2-vinyl-4H-1,3-dithiin, allicin, and S-allyl-cysteine docked well into the <i>NSP3 (SH2D3C)</i>-binding cavity with binding affinities ranging from –4.3~–6.70 Ă and random forest (RF) scores ranging from 4.31~5.26 pKd. However, S-allyl-cysteine interaction with <i>NSP3 (SH2D3C)</i> is unfavorable and hence less susceptible to <i>NSP3</i> ligandability. In conclusion, our study revealed that <i>NSP3</i> is an important onco-immunological biomarker encompassing the tumor microenvironment, disease staging and prognosis in lung cancer and could serve as an attractive target for cancer therapy. The organosulfur compounds from <i>A. sativum</i> have molecular properties to efficiently interact with the binding site of <i>NSP3</i> and are currently under vigorous preclinical study in our laboratory.Yuan-Chieh YehBashir LawalMichael HsiaoTse-Hung HuangChi-Ying F. HuangMDPI AGarticle<i>NSP3 (SH2D3C)</i>NSCLCtumor microenvironmentimmune infiltrationsdysfunctional T-cell phenotypesin silico studyBiology (General)QH301-705.5ENBiomedicines, Vol 9, Iss 1582, p 1582 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>NSP3 (SH2D3C)</i> NSCLC tumor microenvironment immune infiltrations dysfunctional T-cell phenotypes in silico study Biology (General) QH301-705.5
spellingShingle	<i>NSP3 (SH2D3C)</i> NSCLC tumor microenvironment immune infiltrations dysfunctional T-cell phenotypes in silico study Biology (General) QH301-705.5 Yuan-Chieh Yeh Bashir Lawal Michael Hsiao Tse-Hung Huang Chi-Ying F. Huang Identification of <i>NSP3</i> (<i>SH2D3C</i>) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from <i>Allium sativum</i> L. as Therapeutic Candidates
description	The multi-domain non-structural protein 3 (<i>NSP3</i>) is an oncogenic molecule that has been concomitantly implicated in the progression of coronavirus infection. However, its oncological role in lung cancer and whether it plays a role in modulating the tumor immune microenvironment is not properly understood. In the present in silico study, we demonstrated that <i>NSP3 (SH2D3C)</i> is associated with advanced stage and poor prognoses of lung cancer cohorts. Genetic alterations of <i>NSP3 (SH2D3C</i>) co-occurred inversely with Epidermal Growth Factor Receptor (<i>EGFR</i>) alterations and elicited its pathological role via modulation of various components of the immune and inflammatory pathways in lung cancer. Our correlation analysis suggested that <i>NSP3 (SH2D3C)</i> promotes tumor immune evasion via dysfunctional T-cell phenotypes and T-cell exclusion mechanisms in lung cancer patients. <i>NSP3 (SH2D3C)</i> demonstrated a high predictive value and association with therapy resistance in lung cancer, hence serving as an attractive target for therapy exploration. We evaluated the in silico drug-likeness and <i>NSP3 (SH2D3C)</i> target efficacy of six organosulfur small molecules from <i>Allium sativum</i> using a molecular docking study. We found that the six organosulfur compounds demonstrated selective cytotoxic potential against cancer cell lines and good predictions for ADMET properties, drug-likeness, and safety profile. E-ajoene, alliin, diallyl sulfide, 2-vinyl-4H-1,3-dithiin, allicin, and S-allyl-cysteine docked well into the <i>NSP3 (SH2D3C)</i>-binding cavity with binding affinities ranging from –4.3~–6.70 Ă and random forest (RF) scores ranging from 4.31~5.26 pKd. However, S-allyl-cysteine interaction with <i>NSP3 (SH2D3C)</i> is unfavorable and hence less susceptible to <i>NSP3</i> ligandability. In conclusion, our study revealed that <i>NSP3</i> is an important onco-immunological biomarker encompassing the tumor microenvironment, disease staging and prognosis in lung cancer and could serve as an attractive target for cancer therapy. The organosulfur compounds from <i>A. sativum</i> have molecular properties to efficiently interact with the binding site of <i>NSP3</i> and are currently under vigorous preclinical study in our laboratory.
format	article
author	Yuan-Chieh Yeh Bashir Lawal Michael Hsiao Tse-Hung Huang Chi-Ying F. Huang
author_facet	Yuan-Chieh Yeh Bashir Lawal Michael Hsiao Tse-Hung Huang Chi-Ying F. Huang
author_sort	Yuan-Chieh Yeh
title	Identification of <i>NSP3</i> (<i>SH2D3C</i>) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from <i>Allium sativum</i> L. as Therapeutic Candidates
title_short	Identification of <i>NSP3</i> (<i>SH2D3C</i>) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from <i>Allium sativum</i> L. as Therapeutic Candidates
title_full	Identification of <i>NSP3</i> (<i>SH2D3C</i>) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from <i>Allium sativum</i> L. as Therapeutic Candidates
title_fullStr	Identification of <i>NSP3</i> (<i>SH2D3C</i>) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from <i>Allium sativum</i> L. as Therapeutic Candidates
title_full_unstemmed	Identification of <i>NSP3</i> (<i>SH2D3C</i>) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from <i>Allium sativum</i> L. as Therapeutic Candidates
title_sort	identification of <i>nsp3</i> (<i>sh2d3c</i>) as a prognostic biomarker of tumor progression and immune evasion for lung cancer and evaluation of organosulfur compounds from <i>allium sativum</i> l. as therapeutic candidates
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/c7fcc56987a24b0b9f044b50734d6b57
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Identification of <i>NSP3</i> (<i>SH2D3C</i>) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from <i>Allium sativum</i> L. as Therapeutic Candidates

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