Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis.
JCI Insight
; 6(17)2021 09 08.
Article
en En
| MEDLINE
| ID: mdl-34375307
ABSTRACT
Development of primary liver cancer is a multistage process. Detailed understanding of sequential epigenetic alterations is largely missing. Here, we performed Infinium Human Methylation 450k BeadChips and RNA-Seq analyses for genome-wide methylome and transcriptome profiling of cirrhotic liver (n = 7), low- (n = 4) and high-grade (n = 9) dysplastic lesions, and early (n = 5) and progressed (n = 3) hepatocellular carcinomas (HCC) synchronously detected in 8 patients with HCC with chronic hepatitis B infection. Integrative analyses of epigenetically driven molecular changes were identified and validated in 2 independent cohorts comprising 887 HCCs. Mitochondrial DNA sequencing was further employed for clonality analyses, indicating multiclonal origin in the majority of investigated HCCs. Alterations in DNA methylation progressively increased from liver cirrhosis (CL) to dysplastic lesions and reached a maximum in early HCCs. Associated early alterations identified by Ingenuity Pathway Analysis (IPA) involved apoptosis, immune regulation, and stemness pathways, while late changes centered on cell survival, proliferation, and invasion. We further validated 23 putative epidrivers with concomitant expression changes and associated with overall survival. Functionally, Striatin 4 (STRN4) was demonstrated to be epigenetically regulated, and inhibition of STRN4 significantly suppressed tumorigenicity of HCC cell lines. Overall, application of integrative genomic analyses defines epigenetic driver alterations and provides promising targets for potentially novel therapeutic approaches.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Proteínas de Unión a Calmodulina
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Regulación Neoplásica de la Expresión Génica
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Carcinoma Hepatocelular
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Hepatitis B Crónica
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Epigénesis Genética
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Carcinogénesis
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Neoplasias Hepáticas
Tipo de estudio:
Etiology_studies
Límite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
JCI Insight
Año:
2021
Tipo del documento:
Article
País de afiliación:
Alemania