Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carc
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ORIGINAL ARTICLE – CANCER RESEARCH
Aberrant DNA methylation results in altered gene expression in non‑alcoholic steatohepatitis‑related hepatocellular carcinomas Ying Tian1 · Eri Arai1 · Satomi Makiuchi1 · Noboru Tsuda1 · Junko Kuramoto1 · Kentaro Ohara1 · Yoriko Takahashi2 · Nanako Ito1 · Hidenori Ojima1 · Nobuyoshi Hiraoka3 · Masahiro Gotoh4 · Teruhiko Yoshida4 · Yae Kanai1 Received: 30 January 2020 / Accepted: 20 June 2020 © The Author(s) 2020
Abstract Purpose The aim of this study was to investigate DNA methylation alterations in non-alcoholic steatohepatitis (NASH)related hepatocellular carcinomas (HCCs). Methods Genome-wide DNA methylation analysis was performed using the Infinium Human Methylation 450 K BeadChip, and levels of mRNA expression were analyzed by quantitative reverse transcription-PCR. Results Compared to 36 samples of normal control liver tissue (C), DNA methylation alterations were observed on 19,281 probes in 22 samples of cancerous tissue (T) obtained from patients showing histological features compatible with NASH in their non-cancerous liver tissue (N). Among those probes, 1396 were located within CpG islands or their shores and shelves, designed around the transcription start sites of 726 genes. In representative genes, such as DCAF4L2, CKLF, TRIM4, PRC1, UBE2C and TUBA1B, both DNA hypomethylation and mRNA overexpression were observed in T samples relative to C samples, and the levels of DNA methylation and mRNA expression were inversely correlated with each other. DNA hypomethylation occurred even in N samples at the precancerous NASH stage, and this was inherited by or further strengthened in T samples. DNA hypomethylation of DCAF4L2, CKLF and UBE2C was observed in both NASH-related and viral hepatitis-related HCCs, whereas that of TRIM4, PRC1 and TUBA1B occurred in a NASH-related HCC-specific manner. DNA hypomethylation and/or mRNA overexpression of these genes was frequently associated with the necroinflammatory grade of NASH and was correlated with poorer tumor differentiation. Conclusion DNA methylation alterations may occur under the necroinflammatory conditions characteristic of NASH and participate in NASH-related hepatocarcinogenesis through aberrant expression of tumor-related genes. Keywords DNA methylation · Expression alteration · Non-alcoholic steatohepatitis · Hepatocellular carcinoma · DCAF4L2
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00432-020-03298-4) contains supplementary material, which is available to authorized users. * Eri Arai [email protected] 1
Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku‑ku, Tokyo 160‑8582, Japan
2
Bioscience Department, Solution Knowledge Center, Mitsui Knowledge Industry Co., Ltd, Tokyo 105‑6215, Japan
3
Pathology Division, Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104‑0045, Japan
4
Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo 104
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