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Significance of Identifying Key Genes Involved in HBV-Related Hepatocellular Carcinoma for Primary Care Surveillance of Patients with Cirrhosis

Cirrhosis is frequently the final stage of disease preceding the development of hepatocellular carcinoma (HCC) and is one of the risk factors for HCC. Preventive surveillance for early HCC in patients with cirrhosis is advantageous for achieving early HCC prevention and diagnosis, thereby enhancing...

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Autores principales: Li, Yaqun, Li, Jianhua, He, Tianye, Song, Yun, Wu, Jian, Wang, Bin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9778294/
https://www.ncbi.nlm.nih.gov/pubmed/36553600
http://dx.doi.org/10.3390/genes13122331
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author Li, Yaqun
Li, Jianhua
He, Tianye
Song, Yun
Wu, Jian
Wang, Bin
author_facet Li, Yaqun
Li, Jianhua
He, Tianye
Song, Yun
Wu, Jian
Wang, Bin
author_sort Li, Yaqun
collection PubMed
description Cirrhosis is frequently the final stage of disease preceding the development of hepatocellular carcinoma (HCC) and is one of the risk factors for HCC. Preventive surveillance for early HCC in patients with cirrhosis is advantageous for achieving early HCC prevention and diagnosis, thereby enhancing patient prognosis and reducing mortality. However, there is no highly sensitive diagnostic marker for the clinical surveillance of HCC in patients with cirrhosis, which significantly restricts its use in primary care for HCC. To increase the accuracy of illness diagnosis, the study of the effective and sensitive genetic biomarkers involved in HCC incidence is crucial. In this study, a set of 120 significantly differentially expressed genes (DEGs) was identified in the GSE121248 dataset. A protein–protein interaction (PPI) network was constructed among the DEGs, and Cytoscape was used to extract hub genes from the network. In TCGA database, the expression levels, correlation analysis, and predictive performance of hub genes were validated. In total, 15 hub genes showed increased expression, and their positive correlation ranged from 0.80 to 0.90, suggesting they may be involved in the same signaling pathway governing HBV-related HCC. The GSE10143, GSE25097, GSE54236, and GSE17548 datasets were used to investigate the expression pattern of these hub genes in the progression from cirrhosis to HCC. Using Cox regression analysis, a prediction model was then developed. The ROC curves, DCA, and calibration analysis demonstrated the superior disease prediction accuracy of this model. In addition, using proteomic analysis, we investigated whether these key hub genes interact with the HBV-encoded oncogene X protein (HBx), the oncogenic protein in HCC. We constructed stable HBx-expressing LO2-HBx and Huh-7-HBx cell lines. Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS) results demonstrated that CDK1, RRM2, ANLN, and HMMR interacted specifically with HBx in both cell models. Importantly, we investigated 15 potential key genes (CCNB1, CDK1, BUB1B, ECT2, RACGAP1, ANLN, PBK, TOP2A, ASPM, RRM2, NEK2, PRC1, SPP1, HMMR, and DTL) participating in the transformation process of HBV infection to HCC, of which 4 hub genes (CDK1, RRM2, ANLN, and HMMR) probably serve as potential oncogenic HBx downstream target molecules. All these findings of our study provided valuable research direction for the diagnostic gene detection of HBV-related HCC in primary care surveillance for HCC in patients with cirrhosis.
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spelling pubmed-97782942022-12-23 Significance of Identifying Key Genes Involved in HBV-Related Hepatocellular Carcinoma for Primary Care Surveillance of Patients with Cirrhosis Li, Yaqun Li, Jianhua He, Tianye Song, Yun Wu, Jian Wang, Bin Genes (Basel) Article Cirrhosis is frequently the final stage of disease preceding the development of hepatocellular carcinoma (HCC) and is one of the risk factors for HCC. Preventive surveillance for early HCC in patients with cirrhosis is advantageous for achieving early HCC prevention and diagnosis, thereby enhancing patient prognosis and reducing mortality. However, there is no highly sensitive diagnostic marker for the clinical surveillance of HCC in patients with cirrhosis, which significantly restricts its use in primary care for HCC. To increase the accuracy of illness diagnosis, the study of the effective and sensitive genetic biomarkers involved in HCC incidence is crucial. In this study, a set of 120 significantly differentially expressed genes (DEGs) was identified in the GSE121248 dataset. A protein–protein interaction (PPI) network was constructed among the DEGs, and Cytoscape was used to extract hub genes from the network. In TCGA database, the expression levels, correlation analysis, and predictive performance of hub genes were validated. In total, 15 hub genes showed increased expression, and their positive correlation ranged from 0.80 to 0.90, suggesting they may be involved in the same signaling pathway governing HBV-related HCC. The GSE10143, GSE25097, GSE54236, and GSE17548 datasets were used to investigate the expression pattern of these hub genes in the progression from cirrhosis to HCC. Using Cox regression analysis, a prediction model was then developed. The ROC curves, DCA, and calibration analysis demonstrated the superior disease prediction accuracy of this model. In addition, using proteomic analysis, we investigated whether these key hub genes interact with the HBV-encoded oncogene X protein (HBx), the oncogenic protein in HCC. We constructed stable HBx-expressing LO2-HBx and Huh-7-HBx cell lines. Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS) results demonstrated that CDK1, RRM2, ANLN, and HMMR interacted specifically with HBx in both cell models. Importantly, we investigated 15 potential key genes (CCNB1, CDK1, BUB1B, ECT2, RACGAP1, ANLN, PBK, TOP2A, ASPM, RRM2, NEK2, PRC1, SPP1, HMMR, and DTL) participating in the transformation process of HBV infection to HCC, of which 4 hub genes (CDK1, RRM2, ANLN, and HMMR) probably serve as potential oncogenic HBx downstream target molecules. All these findings of our study provided valuable research direction for the diagnostic gene detection of HBV-related HCC in primary care surveillance for HCC in patients with cirrhosis. MDPI 2022-12-10 /pmc/articles/PMC9778294/ /pubmed/36553600 http://dx.doi.org/10.3390/genes13122331 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Li, Yaqun
Li, Jianhua
He, Tianye
Song, Yun
Wu, Jian
Wang, Bin
Significance of Identifying Key Genes Involved in HBV-Related Hepatocellular Carcinoma for Primary Care Surveillance of Patients with Cirrhosis
title Significance of Identifying Key Genes Involved in HBV-Related Hepatocellular Carcinoma for Primary Care Surveillance of Patients with Cirrhosis
title_full Significance of Identifying Key Genes Involved in HBV-Related Hepatocellular Carcinoma for Primary Care Surveillance of Patients with Cirrhosis
title_fullStr Significance of Identifying Key Genes Involved in HBV-Related Hepatocellular Carcinoma for Primary Care Surveillance of Patients with Cirrhosis
title_full_unstemmed Significance of Identifying Key Genes Involved in HBV-Related Hepatocellular Carcinoma for Primary Care Surveillance of Patients with Cirrhosis
title_short Significance of Identifying Key Genes Involved in HBV-Related Hepatocellular Carcinoma for Primary Care Surveillance of Patients with Cirrhosis
title_sort significance of identifying key genes involved in hbv-related hepatocellular carcinoma for primary care surveillance of patients with cirrhosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9778294/
https://www.ncbi.nlm.nih.gov/pubmed/36553600
http://dx.doi.org/10.3390/genes13122331
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