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Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma.
Liu, Zhi-Yong; Lin, Xia-Hui; Guo, Hong-Ying; Shi, Xuan; Zhang, Dan-Ying; Sun, Jia-Lei; Zhang, Guang-Cong; Xu, Ru-Chen; Wang, Fu; Yu, Xiang-Nan; Wang, Dou; Weng, Shu-Qiang; Shen, Xi-Zhong; Liu, Tao-Tao; Dong, Ling; Zhu, Ji-Min.
Afiliación
  • Liu ZY; Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200030, China.
  • Lin XH; Shanghai Institute of Liver Diseases, Shanghai 200030, China.
  • Guo HY; Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200030, China.
  • Shi X; Shanghai Institute of Liver Diseases, Shanghai 200030, China.
  • Zhang DY; Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200030, China.
  • Sun JL; Shanghai Institute of Liver Diseases, Shanghai 200030, China.
  • Zhang GC; Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200030, China.
  • Xu RC; Shanghai Institute of Liver Diseases, Shanghai 200030, China.
  • Wang F; Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200030, China.
  • Yu XN; Shanghai Institute of Liver Diseases, Shanghai 200030, China.
  • Wang D; Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200030, China.
  • Weng SQ; Shanghai Institute of Liver Diseases, Shanghai 200030, China.
  • Shen XZ; Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200030, China.
  • Liu TT; Shanghai Institute of Liver Diseases, Shanghai 200030, China.
  • Dong L; Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200030, China.
  • Zhu JM; Shanghai Institute of Liver Diseases, Shanghai 200030, China.
Int J Biol Sci ; 20(7): 2763-2778, 2024.
Article en En | MEDLINE | ID: mdl-38725845
ABSTRACT
Dysregulation of the aldehyde dehydrogenase (ALDH) family has been implicated in various pathological conditions, including cancer. However, a systematic evaluation of ALDH alterations and their therapeutic relevance in hepatocellular carcinoma (HCC) remains lacking. Herein, we found that 15 of 19 ALDHs were transcriptionally dysregulated in HCC tissues compared to normal liver tissues. A four gene signature, including ALDH2, ALDH5A1, ALDH6A1, and ALDH8A1, robustly predicted prognosis and defined a high-risk subgroup exhibiting immunosuppressive features like regulatory T cell (Tregs) infiltration. Single-cell profiling revealed selective overexpression of tumor necrosis factor receptor superfamily member 18 (TNFRSF18) on Tregs, upregulated in high-risk HCC patients. We identified ALDH2 as a tumor suppressor in HCC, with three novel phosphorylation sites mediated by protein kinase C zeta that enhanced enzymatic activity. Mechanistically, ALDH2 suppressed Tregs differentiation by inhibiting ß-catenin/TGF-ß1 signaling in HCC. Collectively, our integrated multi-omics analysis defines an ALDH-Tregs-TNFRSF18 axis that contributes to HCC pathogenesis and represents potential therapeutic targets for this aggressive malignancy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T Reguladores / Carcinoma Hepatocelular / Aldehído Deshidrogenasa Mitocondrial / Neoplasias Hepáticas Límite: Animals / Humans / Male Idioma: En Revista: Int J Biol Sci Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T Reguladores / Carcinoma Hepatocelular / Aldehído Deshidrogenasa Mitocondrial / Neoplasias Hepáticas Límite: Animals / Humans / Male Idioma: En Revista: Int J Biol Sci Asunto de la revista: BIOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Australia