Downregulation of 15-PGDH enhances MASH-HCC development via fatty acid-induced T-cell exhaustion

Xichen Hu; Tadahito Yasuda; Noriko Yasuda-Yosihara; Atsuko Yonemura; Terumasa Umemoto; Yutaka Nakachi; Kohei Yamashita; Takashi Semba; Kota Arima; Tomoyuki Uchihara; Akiho Nishimura; Luke Bu; Lingfeng Fu; Feng Wei; Jun Zhang; Yilin Tong; Huaitao Wang; Kazuya Iwamoto; Takaichi Fukuda; Hayato Nakagawa; Koji Taniguchi; Yuji Miyamoto; Hideo Baba; Takatsugu Ishimoto

doi:10.1016/j.jhepr.2023.100892

Downregulation of 15-PGDH enhances MASH-HCC development via fatty acid-induced T-cell exhaustion

JHEP Rep. 2023 Aug 23;5(12):100892. doi: 10.1016/j.jhepr.2023.100892. eCollection 2023 Dec.

Authors

Xichen Hu^{1

2}, Tadahito Yasuda^{1

2}, Noriko Yasuda-Yosihara^{1

2}, Atsuko Yonemura^{1

2

3}, Terumasa Umemoto⁴, Yutaka Nakachi⁵, Kohei Yamashita^{1

2}, Takashi Semba^{1

3}, Kota Arima², Tomoyuki Uchihara^{1

2}, Akiho Nishimura^{1

3

6}, Luke Bu^{1

2}, Lingfeng Fu^{1

2

3}, Feng Wei^{1

2}, Jun Zhang^{1

2}, Yilin Tong^{1

2

3}, Huaitao Wang^{1

2

3}, Kazuya Iwamoto⁵, Takaichi Fukuda⁷, Hayato Nakagawa⁸, Koji Taniguchi⁹, Yuji Miyamoto², Hideo Baba^{2

10}, Takatsugu Ishimoto^{1

2

3}

Affiliations

¹ Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
² Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
³ Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁴ Hematopoietic Stem Cell Engineering, International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
⁵ Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
⁶ Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
⁷ Department of Anatomy and Neurobiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
⁸ Department of Gastroenterology and Hepatology, Mie University, Mie, Japan.
⁹ Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
¹⁰ Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Abstract

Background & aims: Hepatocellular carcinoma (HCC) mainly develops from chronic hepatitis. Metabolic dysfunction-associated steatohepatitis (MASH) has gradually become the main pathogenic factor for HCC given the rising incidence of obesity and metabolic diseases. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) degrades prostaglandin 2 (PGE2), which is known to exacerbate inflammatory responses. However, the role of PGE2 accumulation caused by 15-PGDH downregulation in the development of MASH-HCC has not been determined.

Methods: We utilised the steric animal model to establish a MASH-HCC model using wild-type and 15-Pgdh^+/- mice to assess the significance of PGE2 accumulation in the development of MASH-HCC. Additionally, we analysed clinical samples obtained from patients with MASH-HCC.

Results: PGE2 accumulation in the tumour microenvironment induced the production of reactive oxygen species in macrophages and the expression of cell growth-related genes and antiapoptotic genes. Conversely, the downregulation of fatty acid metabolism in the background liver promoted lipid accumulation in the tumour microenvironment, causing a decrease in mitochondrial membrane potential and CD8+ T-cell exhaustion, which led to enhanced development of MASH-HCC.

Conclusions: 15-PGDH downregulation inactivates immune surveillance by promoting the proliferation of exhausted effector T cells, which enhances hepatocyte survival and proliferation and leads to the development of MASH-HCC.

Impact and implications: The suppression of PGE2-related inflammation and subsequent lipid accumulation leads to a reduction in the severity of MASH and inhibition of subsequent progression toward MASH-HCC.

Keywords: 15-Hydroxyprostaglandin dehydrogenase; CD8+ T-cell exhaustion; Chronic inflammation; Cyclooxygenase 2; Metabolic dysfunction associated steatohepatitis-hepatocellular carcinoma; Nonalcoholic steatohepatitis-hepatocellular carcinoma; Prostaglandin E2.