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  3. Extracellular vesicle-mediated communication between hepatocytes and natural killer cells promotes hepatocellular tumorigenesis

Extracellular vesicle-mediated communication between hepatocytes and natural killer cells promotes hepatocellular tumorigenesis

  • Mol Ther. 2022 Feb 2;30(2):606-620. doi: 10.1016/j.ymthe.2021.07.015.
Zhijun Liu 1,  Yuyu You 2,  Qiyi Chen 2,  Guobang Li 3,  Wenfeng Pan 2,  Qing Yang 2,  Jiajun Dong 4,  Yi Wu 4,  Jin-Xin Bei 5,  Chaoyun Pan 6,  Fuming Li 7,  Bo Li 8
Affiliations

Affiliations

  • 1 Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
  • 2 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
  • 3 Department of Urology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
  • 4 Department of Neurosurgery, Jiangmen Central Hospital, Affiliated Jiangmen Hospital, Sun Yat-sen University, Guangdong 529030, China.
  • 5 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510080, China; Center for Precision Medicine, Sun Yat-sen University, Guangzhou 510080, China.
  • 6 Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: panchy27@mail.sysu.edu.cn.
  • 7 Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: fumingli@pennmedicine.upenn.edu.
  • 8 Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510080, China; Center for Precision Medicine, Sun Yat-sen University, Guangzhou 510080, China; RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China. Electronic address: libo47@mail.sysu.edu.cn.
PMID: 34601133 DOI: 10.1016/j.ymthe.2021.07.015
Abstract

Hepatocellular carcinoma (HCC) is frequently characterized by metabolic and immune remodeling in the tumor microenvironment. We previously discovered that liver-specific deletion of fructose-1, 6-bisphosphatase 1 (FBP1), a gluconeogenic Enzyme ubiquitously suppressed in HCC tissues, promotes liver tumorigenesis and induces metabolic and immune perturbations closely resembling human HCC. However, the underlying mechanisms remain incompletely understood. Here, we reported that FBP1-deficient livers exhibit diminished amounts of natural killer (NK) cells and accelerated tumorigenesis. Using the diethylnitrosamine-induced HCC mouse model, we analyzed potential changes in the immune cell populations purified from control and FBP1-depleted livers and found that NK cells were strongly suppressed. Mechanistically, FBP1 attenuation in hepatocytes derepresses an zeste homolog 2 (EZH2)-dependent transcriptional program to inhibit PKLR expression. This leads to reduced levels of PKLR cargo proteins sorted into hepatocyte-derived extracellular vesicles (EVs), dampened activity of EV-targeted NK cells, and accelerated liver tumorigenesis. Our study demonstrated that hepatic FBP1 depletion promotes HCC-associated immune remodeling, partly through the transfer of hepatocyte-secreted, PKLR-attenuated EVs to NK cells.

Keywords

FBP1; PKLR; extracellular vehicles; hepatocellular carcinoma; natural killer cells.

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