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首页> 外文期刊>World Journal of Gastroenterology >Reactive oxygen species-induced activation of Yes-associated protein-1 through the c-Myc pathway is a therapeutic target in hepatocellular carcinoma
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Reactive oxygen species-induced activation of Yes-associated protein-1 through the c-Myc pathway is a therapeutic target in hepatocellular carcinoma

机译：通过C-MYC途径诱导反应性氧物种诱导的是 - MYC途径的活化是肝细胞癌中的治疗靶标

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BACKGROUND The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1 (YAP-1). Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis. The levels of reactive oxygen species (ROS) increase during the progression from early to advanced hepatocellular carcinoma (HCC). AIM To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway. METHODS The expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761) was quantified using real-time polymerase chain reaction and immunoblotting. Human HCC cells were treated with Hsub2/subOsub2/sub, which is a major component of ROS in living organisms, and with either YAP-1 small interfering RNA (siRNA) or control siRNA. To investigate the role of YAP-1 in HCC cells under oxidative stress, MTS assays were performed. Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1. Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses. RESULTS Hsub2/subOsub2/sub treatment increased the mRNA and protein expression of YAP-1 in HCC cells (Huh-7, HepG2, and SNU-761). Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during Hsub2/subOsub2/sub treatment both in vitro and in vivo (both P 0.05). The oncogenic action of YAP-1 occurred via the activation of the c-Myc pathway, leading to the upregulation of components of the unfolded protein response (UPR), including 78-kDa glucose-regulated protein and activating transcription factor-6 (ATF-6). The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues ( P 0.05) and were positively correlated with the ATF-6 Levels (Pearson’s coefficient = 0.299; P 0.05). CONCLUSION This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC. The ROS-induced activation of YAP-1 via the c-Myc pathway, which leads to the activation of the UPR pathway, might be a therapeutic target in HCC.
机译：背景技术河马信号通路通过调节细胞增殖和具有终端效应器的细胞凋亡来调节器官尺寸，包括临时效应器（包括Yes相关蛋白-1（YAP-1）。河马途径中的失调途径已被提出为肝癌发生中的治疗靶标之一。从早期到晚期肝细胞癌（HCC）的进展期间，活性氧物种（ROS）的水平增加。目的通过ROS诱导的HCC损伤和所涉及的信号通路的损伤来研究YAP-1的激活。方法使用实时聚合酶链反应和免疫印迹，量化HCC细胞（Huh-7，HepG2和Snu-761）中YAP-1的表达。用H 2 O 2 处理人HCC细胞，其是生物体中ROS的主要成分，以及YAP-1小干扰RNA（siRNA）或对照siRNA。为了研究YAP-1在HCC细胞在氧化应激下的作用，进行MTS测定。进行免疫印迹以评估负责yap-1活化的信号通路。八十八个手术切除的冷冻HCC组织样品和88个Nontumor肝组织样品用于基因表达分析。结果H 2 O 2 治疗增加了HCC细胞中YAP-1的mRNA和蛋白表达（HUH-7，Hepg2和Snu-761）。使用siRNA转染的YAP-1的抑制导致H 2℃的肿瘤增殖显着降低，体外和体内（P <0.05）。 YAP-1的致癌作用通过C-MYC途径的活化发生，导致展开蛋白质反应（UPR）的组分的上调，包括78-KDA葡萄糖调节蛋白和激活转录因子-6（ATF- 6）。与Nontumor组织中的那些（P <0.05）相比，人HCC组织中的YAP-1 mRNA水平升高了2.6倍，并与ATF-6水平正相关（Pearson系数= 0.299; P <0.05）。结论本研究显示了在HCC氧化应激期间通过C-MYC途径的YAP-1和UPR之间的新连接。通过C-MYC途径的ROS诱导的YAP-1活化，这导致UPR途径的激活，可能是HCC中的治疗靶标。

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