Multi-omics analysis uncovers molecular drivers of non-viral liver cancer development

Researchers discover that inflammation and aging contribute to non-viral liver cancer development. Green tea's role in reversing some of the pathway dysregulation that may contribute to the cancer development and other therapies explored. 

Liver cancer can arise spontaneously from healthy liver tissue. Recently, however, researchers have discovered an increasing correlation between some liver cancers and non-viral chronic liver disease (CLD).

One liver cancer, hepatocellular carcinoma (HCC), is associated with CLD in about 15–25% of cases. While increasing awareness and screening of cancers has improved the ability to detect liver cancer at earlier stages when it is more effectively treated, cancer prevention is always a primary goal of both healthcare providers and biomedical researchers.

The increasing prevalence of CLD with HCC suggests that this underlying condition predisposes liver tissue to cancer development. In order to investigate how healthy liver tissue differs from that of HCC patients with CLD, scientists from Hiroshima University, Hiroshima Prefectural Hospital, and Hiroshima University Hospital compared the gene expression and metabolites (molecules) in normal and affected samples. The team published their research on February 21 in the Journal of Proteome Research.

In this study, we analyzed non-cancerous liver tissue adjacent to HCC lesions from patients with non-viral chronic liver disease. Through multi-omics analysis of transcriptomic and metabolomic data, we aimed to uncover molecular mechanisms underlying HCC development and identify novel targets for chemoprevention."

Hikaru Nakahara, graduate student in the Graduate School of Biomedical and Health Sciences at Hiroshima University, Japan and first author of the research paper

Specifically, the team used RNA-seq to sequence RNA transcripts, or temporary copies of genetic information, to determine which genes were being expressed in normal and CLD tissue and at what levels. By comparing the number of times each RNA transcript was sequenced in each tissue, the researchers could deduce how gene expression differed between the two tissues and infer which cellular pathways may be contributing to disease.

In parallel, the researchers analyzed which metabolites were present in CLD and normal tissue to identify metabolic pathways that may be dysregulated. By investigating differences in gene expression and metabolites, the investigators were able to identify possible disease-causing pathways and potential therapeutic targets for HCC prevention.

"The molecular mechanisms underlying the development of HCC from CLD have been shown to involve activation of inflammation-related signals and age-related metabolic abnormalities. It is suggested that there is a need to distinguish targets for chemoprevention based on these different mechanisms. In addition, it has been suggested that supplementation with antioxidants, such as epigallocatechin gallate (EGCG), may be effective in ameliorating these abnormalities," said Atsushi Ono, lecturer in the Graduate School of Biomedical and Health Sciences at Hiroshima University and an author of the research paper.

The research team categorized CLD cases into two subtypes: Subtype 1, characterized by higher expression of inflammatory markers, and Subtype 2, which is associated with more elderly patients. The elevated inflammatory signaling exhibited by Subtype 1 has already been reported as a potential mechanism for cancer development in previous studies. Both CLD subtypes showed lower gene expression associated with fatty acid metabolism, and Subtype 2 showed higher fatty acid accumulation and metabolite deficiencies compared to normal liver tissue.

Green tea's role in reversing liver disease-linked changes, other therapies explored

Importantly, dysregulation in cellular pathways linked to CLD may offer therapeutic targets for HCC prevention. The research team examined how the gene expression observed in CLD subtypes could be altered by specific treatments. A previously published study using a high-fat diet-induced non-alcoholic fatty liver mouse model showed that green tea or epigallocatechin gallate (EGCG) prevented the increased expression of inflammatory pathways. EGCG may therefore help reverse some of the pathway dysregulation seen in CLD that may contribute to HCC development.

The team acknowledges that more work is required to establish the efficacy of potential therapies for HCC prevention. "In the future, we hope that treatments will be developed that are tailored to molecular abnormalities, such as eliminating inflammation in the [CLD] group characterized by inflammation, and replenishing [metabolites] that become deficient with age in the [CLD] group characterized by aging," said Ono.

Other contributors to this research are C. Nelson Hayes, Yuki Shirane, Ryoichi Miura, Yosuke Tamura, Shinsuke Uchikawa, Hatsue Fujino, Eisuke Murakami, Tomokazu Kawaoka, Daiki Miki, and Shiro Oka from the Department of Gastroenterology in the Graduate School of Biomedical & Health Sciences at Hiroshima University in Hiroshima, Japan; Yasutoshi Fujii from the Departments of Gastroenterology and Clinical Oncology at the Graduate School of Biomedical & Health Sciences at Hiroshima University; Takashi Nakahara from Hiroshima Prefectural Hospital Gastroenterology & Hepatology in Hiroshima, Japan; Masami Yamauchi from the Department of Clinical Oncology, at Hiroshima Prefectural Hospital; Masataka Tsuge from the Department of Gastroenterology in the Graduate School of Biomedical & Health Sciences at Hiroshima University and the Liver Center at Hiroshima University Hospital in Hiroshima, Japan; Tsuyoshi Kobayashi and Hideki Ohdan from the Department of Gastroenterological and Transplant Surgery in the Graduate School of Biomedical and Health Sciences at Hiroshima University; and Koji Arihiro from the Department of Anatomical Pathology at Hiroshima University Hospital.

This work was supported by AMED under Grant Number JP24fk0210130 and the JSPS Program for Forming Japan's Peak Research Universities (JSPS J-PEAKS).