DNA Methylation Status of the SPHK1 and LTB Genes Underlies the Clinicopathological Diversity of Non-alcoholic Steatohepatitis-related Hepatocellular Carcinomas

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2022 Nov 8

PMID 36348017

Authors

Noboru Tsuda

Ying Tian

Mao Fujimoto

Junko Kuramoto

Satomi Makiuchi

Hidenori Ojima

Masahiro Gotoh

Nobuyoshi Hiraoka

Teruhiko Yoshida

Yae Kanai

Eri Arai

Affiliations

Soon will be listed here.

Abstract

Purpose: This study was performed to identify the DNA methylation profiles underlying the clinicopathological diversity of non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinomas (HCCs). METHODS: Genome-wide DNA methylation analysis of 88 liver tissue samples was performed using the Infinium assay.

Results: Principal component analysis revealed that distinct DNA methylation profiles differing from such profiles in normal control liver tissue had already been established in non-cancerous liver tissue showing NASH, which is considered to be a precancerous condition. Hierarchical clustering separated 26 NASH-related HCCs into Cluster I (n = 8) and Cluster II (n = 18). Such epigenetic clustering was significantly correlated with histopathological diversity, i.e. poorer tumor differentiation, tumor steatosis and development of a scirrhous HCC component. Significant differences in DNA methylation levels between the two clusters were accumulated in molecular pathways participating in cell adhesion and cytoskeletal remodeling, as well as cell proliferation and apoptosis. Among tumor-related genes characterizing Clusters I and II, differences in the levels of DNA methylation and mRNA expression for the SPHK1, INHBA, LTB and PDE3B genes were correlated with poorer tumor differentiation. 5-Aza-2'-deoxycytidine treatment of HCC cells revealed epigenetic regulation of the SPHK1 and LTB genes. Knockdown experiments showed that SPHK1 promotes cell proliferation, represses apoptosis and enhances migration, whereas LTB enhances migration of HCC cells. DNA hypomethylation resulting in increased expression of SPHK1 and LTB in poorly differentiated HCCs may underlie the aggressive phenotype of such HCCs.

Conclusion: These data indicate that DNA methylation profiles may determine the clinicopathological heterogeneity of NASH-related HCCs via alterations of tumor-related gene expression.

Citing Articles

Molecular pathological approach to cancer epigenomics and its clinical application.

Kanai Y Pathol Int. 2024; 74(4):167-186.

PMID: 38482965 PMC: 11551818. DOI: 10.1111/pin.13418.

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