Connexin 32 dysfunction promotes ethanol-related hepatocarcinogenesis via activation of Dusp1-Erk axis.
Connexin 32 dysfunction promotes ethanol-related hepatocarcinogenesis via activation of Dusp1-Erk axis.
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DOI：
10.18632/oncotarget.6511
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发表时间：
2016-01-12
期刊：
影响因子：
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通讯作者：
Takahashi S
中科院分区：
文献类型：
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作者：
Kato H;Naiki-Ito A;Naiki T;Suzuki S;Yamashita Y;Sato S;Sagawa H;Kato A;Kuno T;Takahashi S
大量的流行病学证据表明，大量饮酒导致肝细胞癌的发生。已有报道表明，连接蛋白32(Cx32)是一种主要的肝细胞缝隙连接蛋白，在慢性肝病中表达下调，在肝癌的发生中具有保护作用。然而，Cx32在酒精相关性肝癌发生中的作用尚不清楚。9周龄Cx32显性阴性转基因(Tg)大鼠及其野生型(Wt)仔鼠在腹腔注射二乙基亚硝胺(200 mg/kg)后，随机给予1%或5%乙醇(Etoh)或水16周。乙醇以剂量依赖的方式显著增加Tg大鼠肝细胞癌和总肿瘤的发生率和多发性，但对Wt大鼠无明显影响。尽管胎盘型谷胱甘肽S转移酶(GST-P)阳性灶的数目和面积在两组间无显著差异，但乙醇只增加了TG大鼠胎盘型GST-P阳性灶的Ki-67标记指数。乙醇可上调Tg和Wt大鼠全肝组织中磷酸化ERK1/2的表达，同时降低ERK1/2抑制物双特异性蛋白磷酸酶1(DUSP1)的表达。免疫荧光染色和定量RT-PCR结果显示，与Wt组大鼠相比，Etoh组大鼠GST-P阳性灶和肝细胞癌组织中磷酸化ERK1/2核仁定位显著增加，DUSP1蛋白和mRNA表达显著降低。这些发现表明，与慢性肝病一样，Cx32功能障碍通过ERK-DUSP1信号的失调促进了无水乙醇相关性肝癌的发生。
There is abundant epidemiological evidence that heavy alcohol intake contributes to hepatocellular carcinoma (HCC) development. Previous reports indicated that connexin 32 (Cx32), which is a major hepatocyte gap junction protein, is down-regulated in chronic liver disease and has a protective role in hepatocarcinogenesis. However, functions of Cx32 in alcohol-related hepatocarcinogenesis have not been clarified. To evaluate them, 9-week-old Cx32 dominant negative transgenic (Tg) rats and their wild-type (Wt) littermates were given 1 % or 5 % ethanol (EtOH) or water ad libitum, for 16 weeks after an intraperitoneal injection of diethylnitrosamine (200 mg/kg). EtOH significantly increased the incidence and multiplicity of HCC and total tumors in a dose-dependent manner in Tg rats, but not in Wt rats. Although the number and area of glutathione S-transferase placental form (GST-P) positive foci were not significantly different between the groups, EtOH increased the Ki-67 labeling indices in GST-P positive foci only in Tg rats. EtOH up-regulated phosphorylated Erk1/2 with decrease of the Erk1/2 inhibitor, dual specificity protein phosphatase 1 (Dusp1) in whole livers of Tg and Wt rats. Immunofluorescence staining and quantitative RT-PCR revealed that EtOH significantly increased nucleolar localization of phosphorylated Erk1/2 and contrastingly reduced Dusp1 protein and mRNA expression in GST-P positive foci and HCC of Tg rats as compared to those of Wt rats. These findings suggest that Cx32 dysfunction like in chronic liver disease promoted EtOH-associated hepatocarcinogenesis through dysregulation of Erk-Dusp1 signaling.