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

• DOI: 10.1016/j.ymthe.2021.07.015
• Publication Date: 2021-10-01T06:58:57Z
• Authors: Zhijun Liu; Yuyu You; Qiyi Chen; Guobang Li; Wenfeng Pan; Qing Yang; Jiajun Dong; Yi Wu; Jin-Xin Bei; Chaoyun Pan; Fuming Li; Bo Li
• Keywords: Extracellular Vesicles; Extracellular vesicles

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 HCC tissues, promotes liver tumorigenesis induces perturbations closely resembling human HCC. However, underlying mechanisms remain incompletely understood. Here, we reported FBP1-deficient livers exhibit diminished amounts natural killer (NK) cells accelerated tumorigenesis. Using diethylnitrosamine-induced mouse model, analyzed potential changes cell populations purified from control FBP1-depleted found NK were strongly suppressed. Mechanistically, FBP1 attenuation hepatocytes derepresses an zeste homolog 2 (EZH2)-dependent transcriptional program to inhibit PKLR expression. This leads reduced levels cargo proteins sorted into hepatocyte-derived extracellular vesicles (EVs), dampened activity EV-targeted cells, Our study demonstrated hepatic depletion HCC-associated remodeling, partly through transfer hepatocyte-secreted, PKLR-attenuated EVs cells.