The mechanistic target of rapamycin complex 1 (mTORC1) acts as a central regulator of metabolic pathways that drive cellular growth. Abnormal activation of mTORC1 occurs at high frequency in human and mouse hepatocellular carcinoma (HCC). DEP domain-containing protein 5 (DEPDC5), a component of GATOR1 complex, is a repressor of amino acid-sensing branch of the mTORC1 pathway. In the current study, we found that persistent activation of hepatic mTORC1 signaling caused by Depdc5 ablation was sufficient to induce a pathological program of liver damage, inflammation and fibrosis that triggers spontaneous HCC development. Take advantage of the combinatory treatment with a single dose of diethylnitrosamine (DEN) and chronic feeding with high-fat diet (HFD), we demonstrated that hepatic depdc5 deletion did not aggravate DEN&HFD induced liver tumorigenesis, probably due to its protective effects on diet-induced liver steatosis. In addition, we further showed that chronic rapamycin treatment did not have any apparent tumor-suppressing effects on DEN&HFD treated control mice, whereas it dramatically reduced the tumor burden in mice with hepatic Depdc5 ablation. This study provides the novel in vivo evidence for Depdc5 deletion mediated mTORC1 hyperactivation in liver tumorigenesis caused by aging or DEN&HFD treatment. Moreover, our findings also propose that pharmacological inhibition of mTORC1 signaling maybe a promising strategy to treat HCC patients with mutations in DEPDC5 gene.

雷帕霉素复合物 1 (mTORC1) 的机制靶点是驱动细胞生长的代谢途径的中心调节剂。mTORC1 的异常激活在人和小鼠肝细胞癌 (HCC) 中以高频率发生。含有 DEP 结构域的蛋白 5 (DEPDC5) 是 GATOR1 复合物的一个组成部分，是 mTORC1 通路氨基酸感应分支的阻遏物。在目前的研究中，我们发现由Depdc5消融引起的肝脏 mTORC1 信号传导的持续激活足以诱导肝损伤、炎症和纤维化的病理过程，从而触发自发性 HCC 发展。利用单剂量二乙基亚硝胺 (DEN) 和高脂饮食 (HFD) 长期喂养的联合治疗，我们证明了肝depdc5缺失不会加重 DEN 和 HFD 诱导的肝肿瘤发生，可能是由于其对饮食诱导的肝脂肪变性的保护作用。此外，我们进一步表明，慢性雷帕霉素治疗对 DEN&HFD 治疗的对照小鼠没有任何明显的肿瘤抑制作用，而它显着降低了肝脏Depdc5消融小鼠的肿瘤负荷。本研究为衰老或 DEN&HFD 治疗引起的肝肿瘤发生中Depdc5缺失介导的 mTORC1 过度激活提供了新的体内证据。此外，我们的研究结果还表明，药理学抑制 mTORC1 信号可能是治疗DEPDC5基因突变的 HCC 患者的有希望的策略。