Identification and Validation of Pyroptosis-Related Gene Signature to Predict Prognosis and Reveal Immune Infiltration in Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and accounts for the fourth common cause of cancer-related deaths. Recently, pyroptosis has been revealed to be involved in the progression of multiple cancers. However, the role of pyroptosis in the HCC prognosis remain...

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Autores principales:	Xiao-Wei Fu, Chun-Qing Song
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	pyroptosis prognosis biomarker immune infiltration drug sensitivity hepatocellular carcinoma Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/58a6b34e5e6c4567bad0cc586e9e2267
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spelling	oai:doaj.org-article:58a6b34e5e6c4567bad0cc586e9e22672021-11-08T04:40:17ZIdentification and Validation of Pyroptosis-Related Gene Signature to Predict Prognosis and Reveal Immune Infiltration in Hepatocellular Carcinoma2296-634X10.3389/fcell.2021.748039https://doaj.org/article/58a6b34e5e6c4567bad0cc586e9e22672021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.748039/fullhttps://doaj.org/toc/2296-634XBackground: Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and accounts for the fourth common cause of cancer-related deaths. Recently, pyroptosis has been revealed to be involved in the progression of multiple cancers. However, the role of pyroptosis in the HCC prognosis remains elusive.Methods: The clinical information and RNA-seq data of the HCC patients were collected from the TCGA-LIHC datasets, and the differential pyroptosis-related genes (PRG) were firstly explored. The univariate Cox regression and consensus clustering were applied to recognize the HCC subtypes. The prognostic PRGs were then submitted to the LASSO regression analysis to build a prognostic model in the TCGA training cohort. We further evaluated the predictive model in the TCGA test cohort and ICGC validation cohort (LIRI-JP). The accuracy of prediction was validated using the Kaplan—Meier (K-M) and receiver operating characteristic (ROC) analyses. The single-sample gene set enrichment analysis (ssGSEA) was used to determine the differential immune cell infiltrations and related pathways. Finally, the expression of the prognostic genes was validated by qRT-PCR in vivo and in vitro.Results: We identified a total of 26 differential PRGs, among which three PRGs comprising GSDME, GPX4, and SCAF11 were subsequently chosen for constructing a prognostic model. This model significantly distinguished the HCC patients with different survival years in the TCGA training, test, and ICGC validation cohorts. The risk score of this model was confirmed as an independent prognostic factor. A nomogram was generated indicating the survival years for each HCC patient. The ssGSEA demonstrated several tumor-infiltrating immune cells to be remarkably associated with the risk scores. The qRT-PCR results also showed the apparent dysregulation of PRGs in HCC. Finally, the drug sensitivity was analyzed, indicating that Lenvatinib might impact the progression of HCC via targeting GSDME, which was also validated in human Huh7 cells.Conclusion: The PRG signature comprised of GSDME, GPX4, and SCAF11 can serve as an independent prognostic factor for HCC patients, which would provide further evidence for more clinical and functional studies.Xiao-Wei FuXiao-Wei FuXiao-Wei FuXiao-Wei FuChun-Qing SongChun-Qing SongChun-Qing SongFrontiers Media S.A.articlepyroptosisprognosisbiomarkerimmune infiltrationdrug sensitivityhepatocellular carcinomaBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pyroptosis prognosis biomarker immune infiltration drug sensitivity hepatocellular carcinoma Biology (General) QH301-705.5
spellingShingle	pyroptosis prognosis biomarker immune infiltration drug sensitivity hepatocellular carcinoma Biology (General) QH301-705.5 Xiao-Wei Fu Xiao-Wei Fu Xiao-Wei Fu Xiao-Wei Fu Chun-Qing Song Chun-Qing Song Chun-Qing Song Identification and Validation of Pyroptosis-Related Gene Signature to Predict Prognosis and Reveal Immune Infiltration in Hepatocellular Carcinoma
description	Background: Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and accounts for the fourth common cause of cancer-related deaths. Recently, pyroptosis has been revealed to be involved in the progression of multiple cancers. However, the role of pyroptosis in the HCC prognosis remains elusive.Methods: The clinical information and RNA-seq data of the HCC patients were collected from the TCGA-LIHC datasets, and the differential pyroptosis-related genes (PRG) were firstly explored. The univariate Cox regression and consensus clustering were applied to recognize the HCC subtypes. The prognostic PRGs were then submitted to the LASSO regression analysis to build a prognostic model in the TCGA training cohort. We further evaluated the predictive model in the TCGA test cohort and ICGC validation cohort (LIRI-JP). The accuracy of prediction was validated using the Kaplan—Meier (K-M) and receiver operating characteristic (ROC) analyses. The single-sample gene set enrichment analysis (ssGSEA) was used to determine the differential immune cell infiltrations and related pathways. Finally, the expression of the prognostic genes was validated by qRT-PCR in vivo and in vitro.Results: We identified a total of 26 differential PRGs, among which three PRGs comprising GSDME, GPX4, and SCAF11 were subsequently chosen for constructing a prognostic model. This model significantly distinguished the HCC patients with different survival years in the TCGA training, test, and ICGC validation cohorts. The risk score of this model was confirmed as an independent prognostic factor. A nomogram was generated indicating the survival years for each HCC patient. The ssGSEA demonstrated several tumor-infiltrating immune cells to be remarkably associated with the risk scores. The qRT-PCR results also showed the apparent dysregulation of PRGs in HCC. Finally, the drug sensitivity was analyzed, indicating that Lenvatinib might impact the progression of HCC via targeting GSDME, which was also validated in human Huh7 cells.Conclusion: The PRG signature comprised of GSDME, GPX4, and SCAF11 can serve as an independent prognostic factor for HCC patients, which would provide further evidence for more clinical and functional studies.
format	article
author	Xiao-Wei Fu Xiao-Wei Fu Xiao-Wei Fu Xiao-Wei Fu Chun-Qing Song Chun-Qing Song Chun-Qing Song
author_facet	Xiao-Wei Fu Xiao-Wei Fu Xiao-Wei Fu Xiao-Wei Fu Chun-Qing Song Chun-Qing Song Chun-Qing Song
author_sort	Xiao-Wei Fu
title	Identification and Validation of Pyroptosis-Related Gene Signature to Predict Prognosis and Reveal Immune Infiltration in Hepatocellular Carcinoma
title_short	Identification and Validation of Pyroptosis-Related Gene Signature to Predict Prognosis and Reveal Immune Infiltration in Hepatocellular Carcinoma
title_full	Identification and Validation of Pyroptosis-Related Gene Signature to Predict Prognosis and Reveal Immune Infiltration in Hepatocellular Carcinoma
title_fullStr	Identification and Validation of Pyroptosis-Related Gene Signature to Predict Prognosis and Reveal Immune Infiltration in Hepatocellular Carcinoma
title_full_unstemmed	Identification and Validation of Pyroptosis-Related Gene Signature to Predict Prognosis and Reveal Immune Infiltration in Hepatocellular Carcinoma
title_sort	identification and validation of pyroptosis-related gene signature to predict prognosis and reveal immune infiltration in hepatocellular carcinoma
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/58a6b34e5e6c4567bad0cc586e9e2267
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Identification and Validation of Pyroptosis-Related Gene Signature to Predict Prognosis and Reveal Immune Infiltration in Hepatocellular Carcinoma

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