Intra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis

While many anti-cancer modalities have shown potent efficacy in clinical practices, cancer prevention, timely detection, and effective treatment are still challenging. As a newly recognized iron-dependent cell death mechanism characterized by excessive generation of lipid peroxidation, ferroptosis i...

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Autores principales:	Jiajun He, Hongjian Ding, Huaqing Li, Zhiyu Pan, Qian Chen
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	ferroptosis SLC7A11 pan-cancer immune microenvironment drug resistance Genetics QH426-470
Acceso en línea:	https://doaj.org/article/bdfc4c688d5f4c4bb03f53bdcf759ea2
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spelling	oai:doaj.org-article:bdfc4c688d5f4c4bb03f53bdcf759ea22021-12-02T11:39:00ZIntra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis1664-802110.3389/fgene.2021.770857https://doaj.org/article/bdfc4c688d5f4c4bb03f53bdcf759ea22021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fgene.2021.770857/fullhttps://doaj.org/toc/1664-8021While many anti-cancer modalities have shown potent efficacy in clinical practices, cancer prevention, timely detection, and effective treatment are still challenging. As a newly recognized iron-dependent cell death mechanism characterized by excessive generation of lipid peroxidation, ferroptosis is regarded as a potent weapon in clearing cancer cells. The cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) is the core target for ferroptosis regulation, the overexpression of which dictates downregulated sensitivity to ferroptosis in cancer cells. Hence, we elaborated the pan-cancer level bioinformatic study and systematically elucidated the role of intra-tumoral expression of SLC7A11 in the survival of cancer patients and potential immunotherapeutic response. Specifically, 25/27 (92.6%) cancers were featured with upregulated SLC7A11 expression, where SLC7A11 overexpression is a risk factor for worse overall survival in 8 cancers. We also validated SLC7A11 expression in multiple pancreatic cancer cell lines in vitro and found that it was upregulated in most pancreatic cancer cell lines (p < 0.05). Single-cell sequencing method revealed the SLC7A11 was majorly expressed in cancer cells and mononuclear cells. To further explore the function of SLC7A11 in cancer progression, we analyzed the influence on cell proliferation after the knockdown or knockout of SLC7A11 by either CRISPR or RNAi methods. Besides, the association between SLC7A11 and drug resistance was characterized using bioinformatic approaches as well. We also analyzed the association between the expression of SLC7A11 in multi-omics level and the intra-tumoral infiltration of immune cells based on cell annotation algorithms. Moreover, the relationship between SLC7A11 and the expression of MHC, immune stimulators, immune inhibitors as well as the response to immunotherapy was investigated. In addition, the SLC7A11 expression in colon adenocarcinoma, uterine corpus endometrial carcinoma, and stomach adenocarcinoma (STAD) is also positively associated with microsatellite instability and that in head and neck squamous cell carcinoma, STAD, and prostate adenocarcinoma is positively associated with neoantigen level, which further revealed the potential relationship between SLC7A11 and immunotherapeutic response.Jiajun HeHongjian DingHuaqing LiZhiyu PanQian ChenFrontiers Media S.A.articleferroptosisSLC7A11pan-cancerimmune microenvironmentdrug resistanceGeneticsQH426-470ENFrontiers in Genetics, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ferroptosis SLC7A11 pan-cancer immune microenvironment drug resistance Genetics QH426-470
spellingShingle	ferroptosis SLC7A11 pan-cancer immune microenvironment drug resistance Genetics QH426-470 Jiajun He Hongjian Ding Huaqing Li Zhiyu Pan Qian Chen Intra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis
description	While many anti-cancer modalities have shown potent efficacy in clinical practices, cancer prevention, timely detection, and effective treatment are still challenging. As a newly recognized iron-dependent cell death mechanism characterized by excessive generation of lipid peroxidation, ferroptosis is regarded as a potent weapon in clearing cancer cells. The cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) is the core target for ferroptosis regulation, the overexpression of which dictates downregulated sensitivity to ferroptosis in cancer cells. Hence, we elaborated the pan-cancer level bioinformatic study and systematically elucidated the role of intra-tumoral expression of SLC7A11 in the survival of cancer patients and potential immunotherapeutic response. Specifically, 25/27 (92.6%) cancers were featured with upregulated SLC7A11 expression, where SLC7A11 overexpression is a risk factor for worse overall survival in 8 cancers. We also validated SLC7A11 expression in multiple pancreatic cancer cell lines in vitro and found that it was upregulated in most pancreatic cancer cell lines (p < 0.05). Single-cell sequencing method revealed the SLC7A11 was majorly expressed in cancer cells and mononuclear cells. To further explore the function of SLC7A11 in cancer progression, we analyzed the influence on cell proliferation after the knockdown or knockout of SLC7A11 by either CRISPR or RNAi methods. Besides, the association between SLC7A11 and drug resistance was characterized using bioinformatic approaches as well. We also analyzed the association between the expression of SLC7A11 in multi-omics level and the intra-tumoral infiltration of immune cells based on cell annotation algorithms. Moreover, the relationship between SLC7A11 and the expression of MHC, immune stimulators, immune inhibitors as well as the response to immunotherapy was investigated. In addition, the SLC7A11 expression in colon adenocarcinoma, uterine corpus endometrial carcinoma, and stomach adenocarcinoma (STAD) is also positively associated with microsatellite instability and that in head and neck squamous cell carcinoma, STAD, and prostate adenocarcinoma is positively associated with neoantigen level, which further revealed the potential relationship between SLC7A11 and immunotherapeutic response.
format	article
author	Jiajun He Hongjian Ding Huaqing Li Zhiyu Pan Qian Chen
author_facet	Jiajun He Hongjian Ding Huaqing Li Zhiyu Pan Qian Chen
author_sort	Jiajun He
title	Intra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis
title_short	Intra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis
title_full	Intra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis
title_fullStr	Intra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis
title_full_unstemmed	Intra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis
title_sort	intra-tumoral expression of slc7a11 is associated with immune microenvironment, drug resistance, and prognosis in cancers: a pan-cancer analysis
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/bdfc4c688d5f4c4bb03f53bdcf759ea2
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_version_	1718395785046917120

Intra-Tumoral Expression of SLC7A11 Is Associated with Immune Microenvironment, Drug Resistance, and Prognosis in Cancers: A Pan-Cancer Analysis

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