Alcohol consumption, Wnt/β-catenin signaling, and hepatocarcinogenesis.
Alcohol consumption, Wnt/β-catenin signaling, and hepatocarcinogenesis.
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DOI：
10.1007/978-3-319-09614-8_11
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发表时间：
2015
影响因子：
--
通讯作者：
Ronis MJ
中科院分区：
文献类型：
--
作者：
Mercer KE;Hennings L;Ronis MJ
酒精是肝细胞癌的一个公认的危险因素，并且酒精性肝癌的发病机制很复杂。有人提出，乙醇（EtOH）代谢可能通过增加肝细胞增殖来促进肿瘤进展。为了检验这一假设，在注射化学致癌物二乙基亚硝胺 (DEN) 7 周后开始对雄性小鼠进行乙醇 (EtOH) 喂养，并持续 16 周，最终 EtOH 浓度为总热量的 28%。正如预期的那样，与相应的配对喂养（PF）+DEN 和食物+DEN 对照组相比，EtOH 增加了 EtOH+DEN 组原位固定肝脏中发现的癌灶和肝脏肿瘤的总数。在EtOH+DEN组中，与PF+DEN和chow+DEN组相比，肿瘤多重性相当于非致瘤性肝细胞中β-连环蛋白的增殖和免疫组织化学染色增加3至4倍，p<0.05。对先前发表的慢性肝病大鼠模型的乙醇处理肝脏进行的分析显示，肝细胞增殖增加，并伴有视黄醇和视黄酸储备的肝脏消耗（p<0.05）、β-连环蛋白核积聚（p<0.05）、胞质表达 p-GSK3β 增加（p<0.05）、可溶性蛋白显着上调。 Wnts、Wnt2 和 Wnt7a，以及参与肿瘤促进和进展的多个 β-连环蛋白靶标、细胞周期蛋白 D1、c-myc、WISP1 和 MMP7 的表达增加 (p<0.05)。这些数据表明，长期消耗乙醇会激活 Wnt/β-连环蛋白信号通路，从而增加肝细胞增殖，从而在肝脏受到初始损伤后促进肿瘤发生。
Alcohol is a well-established risk factor for hepatocellular carcinoma, and the mechanisms by which alcohol liver cancer are complex. It has been suggested that ethanol (EtOH) metabolism may enhance tumor progression by increasing hepatocyte proliferation. To test this hypothesis, ethanol (EtOH) feeding of male mice began 7 weeks post-injection of the chemical carcinogen diethylnitrosamine (DEN), and continued for 16 weeks, with a final EtOH concentration of 28% of total calories. As expected, EtOH increased the total number of cancerous foci and liver tumors identified in situ fixed livers from the EtOH+DEN group compared to corresponding pair-fed (PF) +DEN and chow+DEN control groups. In the EtOH+DEN group, tumor multiplicity corresponded to a 3- to 4-fold increase proliferation and immunohistochemical staining of β-catenin in non-tumorgenic hepatocytes when compared to the PF+DEN and chow+DEN groups, p<0.05. Analysis of EtOH-treated livers from a previously published rat model of chronic liver disease revealed increases in hepatocyte proliferation accompanied by a hepatic depletion of retinol and retinoic acid stores (p<0.05), nuclear accumulation of β-catenin (p<0.05), increased cytosolic expression p-GSK3β (p<0.05), significant up-regulation of soluble Wnts, Wnt2, and Wnt7a, and increased expression of several β-catenin targets involved in tumor promotion and progression, cyclin D1, c-myc, WISP1, and MMP7 (p<0.05). These data suggest that chronic EtOH consumption activates the Wnt/β-catenin signaling pathway, which increase hepatocyte proliferation thus promoting tumorigenesis following an initiating insult in the liver.
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影响因子：
13.5
作者：
Stahl, S;Ittrich, C;Schwarz, M
通讯作者：
Schwarz, M
影响因子：
13.5
作者：
Yanagitani, A;Yamada, S;Shiota, G
通讯作者：
Shiota, G
DOI：
10.1152/ajpgi.00145.2010
发表时间：
2011-01-01
影响因子：
4.5
作者：
Ronis, Martin J. J.;Hennings, Leah;Petersen, Dennis R.
通讯作者：
Petersen, Dennis R.
DOI：
10.1111/j.1530-0277.2011.01660.x
发表时间：
2012-04
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Brandon-Warner E;Walling TL;Schrum LW;McKillop IH
通讯作者：
McKillop IH
影响因子：
14.5
作者：
Nejak-Bowen KN;Monga SP
通讯作者：
Monga SP