Vacuolar Protein Sorting 33B Is a Tumor Suppressor in Hepatocarcinogenesis
Vacuolar Protein Sorting 33B Is a Tumor Suppressor in Hepatocarcinogenesis
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液泡蛋白分选 33B 是肝癌发生中的肿瘤抑制因子
DOI：
10.1002/hep.30077
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发表时间：
2018-12-01
期刊：
影响因子：
13.5
通讯作者：
Liu, Junling
中科院分区：
文献类型：
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作者：
Wang, Conghui;Cheng, Yuqiang;Liu, Junling
极性缺陷经常与肝脏疾病有关，例如慢性肝炎和肝细胞癌（HCC）。据报道，液泡蛋白分选33B（Vps33b）在肝细胞极性的维持中发挥着关键作用；然而，Vps33b 在 HCC 发生和进展中的功能作用和机制仍不清楚。首先，我们发现Vps33b在人和小鼠肝癌样本中下调，Vps33b的低表达水平与许多HCC患者的不良预后相关。肝脏特异性 Vps33b 缺乏会导致雄性小鼠出现肝损伤、进行性肝炎、纤维化和肝癌，这表明 Vps33b 是肝癌发生的关键因素。 Vps33b缺陷引起的肝损伤主要是由于肝细胞结构和功能极性紊乱所致，具体表现为由于溶酶体定位不准确以及顶端和侧质膜蛋白极性缺陷导致E-钙粘蛋白水平下降。机制研究结果表明，Vps33b 与 VPS33B 相互作用蛋白相互作用，VPS33B 相互作用蛋白参与极性和顶端蛋白限制；囊泡运输蛋白 Sec22b；肝细胞中的 Flotillin-1 和 Flotillin-1 负责极性决定蛋白的正常分布。 Vps33b 的表达水平与二乙基亚硝胺诱导的或转基因 HCC 小鼠模型肝脏中炎症细胞浸润的程度呈负相关，并且炎症刺激在体外抑制了 Vps33b 的表达。结论：Vps33b表达下调是炎症驱动的HCC的关键步骤，Vps33b在肝癌发生中是重要的抑癌基因。
Polarity defects are frequently involved in liver diseases, such as chronic hepatitis and hepatocellular carcinoma (HCC). It was reported that vacuolar protein sorting 33B (Vps33b) plays critical roles in the maintenance of hepatocyte polarity; however, the functional roles and mechanisms of Vps33b in HCC occurrence and progression remain unknown. First of all, we showed that Vps33b is down‐regulated in human and mouse liver cancer samples, and the low expression levels of Vps33b correlate with the poor prognosis of many HCC patients. Liver‐specific Vps33b deficiency induces liver damage, progressive hepatitis, fibrosis, and HCC in male mice, indicating that Vps33b is a crucial contributory factor to hepatocarcinogenesis. Vps33b deficiency–caused liver damage was primarily due to the disorders of structural and functional hepatocyte polarity, which were reflected by the decreased protein levels of E‐cadherin because of inaccurate location to lysosomes and polarity defects at both apical and lateral plasma membrane proteins. The results of a mechanism study revealed that Vps33b interacts with VPS33B‐interacting protein, which is involved in polarity and apical protein restriction; vesicle‐trafficking protein Sec22b; and Flotillin‐1 in hepatocytes and is in charge of the normal distribution of polarity‐determined proteins. Expression levels of Vps33b negatively correlated with the degree of inflammatory cell infiltration in livers from diethylnitrosamine‐induced or transgenic HCC mouse models, and the inflammatory stimuli suppressed the expression of Vps33b in vitro. Conclusion: Down‐regulation of Vps33b expression is a critical step for inflammation‐driven HCC, and Vps33b serves as an important tumor suppressor in hepatocarcinogenesis.