Connexin 32 dysfunction promotes ethanol-related hepatocarcinogenesis via activation of Dusp1-Erk axis
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Hiroyuki Kato1, Aya Naiki-Ito1, Taku Naiki1, Shugo Suzuki1, Yoriko Yamashita1, Shinya Sato1, Hiroyuki Sagawa1,2, Akihisa Kato1,3, Toshiya Kuno1, Satoru Takahashi1
1Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
2Department of Gastroenterological Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
3Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
Aya Naiki-Ito, e-mail: firstname.lastname@example.org
Keywords: connexin 32, alcohol, hepatocarcinogenesis, Erk, Dusp1
Received: July 16, 2015 Accepted: November 21, 2015 Published: December 09, 2015
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.
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