Objective Hepatocellular carcinoma (HCC) development occurs with non-alcoholic fatty liver disease (NAFLD) in the absence of cirrhosis and with an increasing incidence due to the obesity pandemic. Mutations of tumour suppressor (TS) genes and oncogenes (ONC) have been widely characterised in HCC. However, mounting evidence indicates that non-genomic alterations of TS/ONC occur early with NAFLD, thereby potentially promoting hepatocarcinogenesis in an inflammatory/fibrotic context. The aim of this study was to identify and characterise these alterations. Design The proteome of steatotic liver tissues from mice spontaneously developing HCC was analysed. Alterations of TSs/ONCs were further investigated in various mouse models of NAFLD/HCC and in human samples. The inflammatory, fibrogenic and oncogenic functions of S100A11 were assessed through in vivo, in vitro and ex-vivo analyses. Results A whole set of TSs/ONCs, respectively, downregulated or upregulated was uncovered in mice and human with NAFLD. Alterations of these TSs/ONCs were preserved or even exacerbated in HCC. Among them, overexpression of S100A11 was associated with high-grade HCC and poor prognosis. S100A11 downregulation in vivo significantly restrains the development of inflammation and fibrosis in mice fed a choline/methionine-deficient diet. Finally, in vitro and ex-vivo analyses revealed that S100A11 is a marker of hepatocyte de-differentiation, secreted by cancer cells, and promoting cell proliferation and migration. Conclusion Cellular stress associated with NAFLD triggers non-genomic alterations of a whole network of TSs/ONCs fostering hepatocarcinogenesis. Among those, overexpression of the oncogenic factor S100A11 promotes inflammation/fibrosis in vivo and is significantly associated with high-grade HCC with poor prognosis.

中文翻译：

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S100A11/ANXA2 属于一个肿瘤抑制/癌基因网络，在脂肪变性早期失调并参与炎症和肝细胞癌的发展

目的 肝细胞癌 (HCC) 与非酒精性脂肪性肝病 (NAFLD) 一起发生，但没有肝硬化，并且由于肥胖大流行，其发病率不断增加。肿瘤抑制 (TS) 基因和癌基因 (ONC) 的突变已在 HCC 中得到广泛表征。然而，越来越多的证据表明 TS/ONC 的非基因组改变在 NAFLD 早期发生，从而可能促进炎症/纤维化背景下的肝癌发生。本研究的目的是确定和表征这些改变。设计 分析了自发发展为 HCC 的小鼠的脂肪变性肝组织的蛋白质组。在各种 NAFLD/HCC 小鼠模型和人类样本中进一步研究了 TSs/ONCs 的变化。发炎的，通过体内、体外和离体分析评估了 S100A11 的纤维化和致癌功能。结果 在患有 NAFLD 的小鼠和人类中发现了一整套分别下调或上调的 TSs/ONCs。这些 TS/ONC 的改变在 HCC 中得以保留甚至加剧。其中，S100A11的过表达与高级别HCC和不良预后相关。S100A11 体内 下调显着抑制了喂食胆碱/蛋氨酸缺乏饮食的小鼠的炎症和纤维化的发展。最后，体外和离体分析表明，S100A11 是肝细胞去分化的标志物，由癌细胞分泌，促进细胞增殖和迁移。结论与 NAFLD 相关的细胞应激触发了整个 TSs/ONCs 网络的非基因组改变，促进了肝癌的发生。其中，致癌因子 S100A11 的过度表达会促进体内炎症/纤维化，并且与预后不良的高级别 HCC 显着相关。