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Identification and validation of novel signature associated with hepatocellular carcinoma prognosis using Single-cell and WGCNA analysis

Background: Hepatocellular carcinoma is a rapidly advancing malignancy with a poor prognosis. Therefore, further research is needed on its potential pathogenesis and therapeutic targets. Methods: In this study, the relevant datasets were downloaded from the TCGA database and the key modules were ide...

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Autores principales: Song, Hang, Ge, Yang, Xu, Jing, Shen, Rui, Zhang, Peng-cheng, Wang, Guo-quan, Liu, Bin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266049/
https://www.ncbi.nlm.nih.gov/pubmed/37324188
http://dx.doi.org/10.7150/ijms.79274
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author Song, Hang
Ge, Yang
Xu, Jing
Shen, Rui
Zhang, Peng-cheng
Wang, Guo-quan
Liu, Bin
author_facet Song, Hang
Ge, Yang
Xu, Jing
Shen, Rui
Zhang, Peng-cheng
Wang, Guo-quan
Liu, Bin
author_sort Song, Hang
collection PubMed
description Background: Hepatocellular carcinoma is a rapidly advancing malignancy with a poor prognosis. Therefore, further research is needed on its potential pathogenesis and therapeutic targets. Methods: In this study, the relevant datasets were downloaded from the TCGA database and the key modules were identified using WGCNA in the necroptosis-related gene set, while single-cell datasets were scored using the necroptosis gene set. Differential genes in the high- and low-expression groups were determined using the WGCNA module genes as intersection sets to identify key genes involved in necroptosis in liver cancer. Then, prognostic models were constructed using LASSO COX regression followed by multi-faceted validation. Finally, model genes were found to be correlated with key proteins of the necroptosis pathway and used to identify the most relevant genes, followed by their experimental validation. Subsequently, on the basis of the analysis results, the most relevant SFPQ was selected for cell-level verification. Results: We constructed a prognosis model that included five necroptosis-related genes (EHD1, RAC1, SFPQ, DAB2 and PABPC4) to predict the prognosis and survival of HCC patients. The results showed that the prognosis was more unfavorable in the high-risk group compared to the low-risk group, which was corroborated using ROC curves and risk factor plots. In addition, we further checked the differential genes using GO and KEGG analyses and found that they were predominantly enriched in the neuroactive ligand-receptor interaction pathway. The results of the GSVA analysis demonstrated that the high-risk group was mainly enriched in DNA replication, regulation of the mitotic cycle, and regulation of various cancer pathways, while the low-risk group was predominantly enriched in the metabolism of drugs and xenobiotics using cytochrome P450. SFPQ was found to be the main gene that affects the prognosis and SFPQ expression was positively correlated with the expression of RIPK1, RIPK3 and MLKL. Furthermore, the suppression of SFPQ could inhibit hyper-malignant phenotype HCC cells, while the WB results showed that inhibition of SFPQ expression also resulted in lower expression of necroptosis proteins, compared to the sh-NC group. Conclusions: Our prognostic model could accurately predict the prognosis of patients with HCC to further identify novel molecular candidates and interventions that can be used as alternative methods of treatment for HCC.
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spelling pubmed-102660492023-06-15 Identification and validation of novel signature associated with hepatocellular carcinoma prognosis using Single-cell and WGCNA analysis Song, Hang Ge, Yang Xu, Jing Shen, Rui Zhang, Peng-cheng Wang, Guo-quan Liu, Bin Int J Med Sci Research Paper Background: Hepatocellular carcinoma is a rapidly advancing malignancy with a poor prognosis. Therefore, further research is needed on its potential pathogenesis and therapeutic targets. Methods: In this study, the relevant datasets were downloaded from the TCGA database and the key modules were identified using WGCNA in the necroptosis-related gene set, while single-cell datasets were scored using the necroptosis gene set. Differential genes in the high- and low-expression groups were determined using the WGCNA module genes as intersection sets to identify key genes involved in necroptosis in liver cancer. Then, prognostic models were constructed using LASSO COX regression followed by multi-faceted validation. Finally, model genes were found to be correlated with key proteins of the necroptosis pathway and used to identify the most relevant genes, followed by their experimental validation. Subsequently, on the basis of the analysis results, the most relevant SFPQ was selected for cell-level verification. Results: We constructed a prognosis model that included five necroptosis-related genes (EHD1, RAC1, SFPQ, DAB2 and PABPC4) to predict the prognosis and survival of HCC patients. The results showed that the prognosis was more unfavorable in the high-risk group compared to the low-risk group, which was corroborated using ROC curves and risk factor plots. In addition, we further checked the differential genes using GO and KEGG analyses and found that they were predominantly enriched in the neuroactive ligand-receptor interaction pathway. The results of the GSVA analysis demonstrated that the high-risk group was mainly enriched in DNA replication, regulation of the mitotic cycle, and regulation of various cancer pathways, while the low-risk group was predominantly enriched in the metabolism of drugs and xenobiotics using cytochrome P450. SFPQ was found to be the main gene that affects the prognosis and SFPQ expression was positively correlated with the expression of RIPK1, RIPK3 and MLKL. Furthermore, the suppression of SFPQ could inhibit hyper-malignant phenotype HCC cells, while the WB results showed that inhibition of SFPQ expression also resulted in lower expression of necroptosis proteins, compared to the sh-NC group. Conclusions: Our prognostic model could accurately predict the prognosis of patients with HCC to further identify novel molecular candidates and interventions that can be used as alternative methods of treatment for HCC. Ivyspring International Publisher 2023-05-11 /pmc/articles/PMC10266049/ /pubmed/37324188 http://dx.doi.org/10.7150/ijms.79274 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Song, Hang
Ge, Yang
Xu, Jing
Shen, Rui
Zhang, Peng-cheng
Wang, Guo-quan
Liu, Bin
Identification and validation of novel signature associated with hepatocellular carcinoma prognosis using Single-cell and WGCNA analysis
title Identification and validation of novel signature associated with hepatocellular carcinoma prognosis using Single-cell and WGCNA analysis
title_full Identification and validation of novel signature associated with hepatocellular carcinoma prognosis using Single-cell and WGCNA analysis
title_fullStr Identification and validation of novel signature associated with hepatocellular carcinoma prognosis using Single-cell and WGCNA analysis
title_full_unstemmed Identification and validation of novel signature associated with hepatocellular carcinoma prognosis using Single-cell and WGCNA analysis
title_short Identification and validation of novel signature associated with hepatocellular carcinoma prognosis using Single-cell and WGCNA analysis
title_sort identification and validation of novel signature associated with hepatocellular carcinoma prognosis using single-cell and wgcna analysis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10266049/
https://www.ncbi.nlm.nih.gov/pubmed/37324188
http://dx.doi.org/10.7150/ijms.79274
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