| Molecular Classification of Hepatocellular Carcinoma based on Zoned Metabolic Feature and Oncogenic Signaling Pathway |
Tomoko Aoki1
, Naoshi Nishida1
, Yutaka Kurebayashi2, Kazuko Sakai1, Naoto Fujiwara4, Masakatsu Tsurusaki5, Kohei Hanaoka6, Masahiro Morita1, Hirokazu Chishina1, Masahiro Takita1, Satoru Hagiwara1, Hiroshi Ida1, Kazuomi Ueshima1, Yasunori Minami1, Atsushi Takebe7, Takaaki Murase7, Keiko Kamei7, Takuya Nakai7, Ippei Matsumoto7, Kazuto Nishio3, Masatoshi Kudo1
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1Department of Gastroenterology and Hepatology/Kindai University Faculty of Medicine, Osaka-Sayama, Japan
2Department of Pathology, Keio University School of Medicine, Tokyo, Japan
3Department of Genome Biology, Kindai University Faculty of Medicine, Osaka, Japan
4Department of Gastroenterology and Hepatology, Mie University, Japan
5Department of Radiology, Kansai Medical University Medical Center, Osaka, Japan
6Institute of Advanced Clinical Medicine, Kindai University, Osaka, Japan
7Department of Surgery, Faculty of Medicine, Kindai University, Osaka, Japan |
| Correspondence : |
Tomoko Aoki ,
Tel: +81-72-366-0221 (Ext. 3149), Fax: +81-72-367-2880, Email: tomoko.aoki@med.kindai.ac.jp
Naoshi Nishida ,
Tel: +81-72-366-0221 (Ext. 3149), Fax: +81-72-367-2880, Masatoshi Kudo ,
Tel: +81-72-366-0221 (Ext. 3149), Fax: +81-72-367-2880, Email: m-kudo@med.kindai.ac.jp
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Received: December 3, 2024 Revised: March 6, 2025 Accepted: March 7, 2025 |
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| ABSTRACT |
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Background/Aims
Previously, we advocated the importance of classifying hepatocellular carcinoma (HCC) based on physiological functions. This study aims to classify HCC by focusing on liver-intrinsic metabolism and glycolytic pathway in cancer cells.
Methods
Comprehensive RNA/DNA sequencing, immunohistochemistry, and radiological evaluations were performed on HCC tissues from the training cohort (n=136) and validated in 916 public samples. HCC was classified using hierarchical clustering and compared with previous molecular, histopathological, and hemodynamic classifications.
Results
Liver-specific metabolism and glycolysis are mutually exclusive and were divided into two major subclasses: The "rich metabolism" subclass (60.3%) is characterized by enhanced bile acid and fatty acid metabolism, well-to-moderate differentiation, microtrabecular or pseudoglandular pattern, and homogeneous arterial-phase hyperenhancement (APHE), corresponding to Hoshida S3 with favorable prognosis. In IL6-JAK-STAT3-high (25.0%) conditions, upregulated ALB expression, enhanced gluconeogenesis and urea cycle activity, and an inflammatory-microenvironment are observed. Conversely, the Wnt/β-catenin-high environment (19.9%) features elevated GLUL, APOB and CYP3A4 expression, frequent CTNNB1 (D32-S37) mutations, and an immune-desert/excluded phenotype. The "glycolysis" subclass (39.7%), characterized by histopathological dedifferentiation and downregulated liver-specific metabolism, encompasses subclasses with PI3K/mTOR (20.6%) and NOTCH/TGF-β (19.1%) signaling. These often exhibit TP53 mutations, macrotrabecular massive or compact patterns, inhomogeneous/rim-APHE, and high expression of hypoxia-inducible factors and glucose transporters, corresponding to Hoshida S1/2 with poor prognosis.
Conclusions
The loss of liver-specific metabolism correlates with morphological dedifferentiation, indicating cellular dedifferentiation may exhibit both physiological and pathological duality. Key signaling pathways involved in the maturation process from fetal to adult liver and zonation program may play a critical role in defining HCC diversity. |
| KeyWords:
carcinoma, hepatocellular, cell differentiation, bile acids and salts, metabolism, glycolysis, Warburg effect, oncologic, neoplasms by histologic type, molecular diagnostic techniques, gene expression profiling, RNA-Seq, transcriptome, sequence analysis, RNA, multiomics, genomics, tumor microenvironment |
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