Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription.
Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription.
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DOI：
10.1126/scitranslmed.3001143
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发表时间：
2010-05-19
影响因子：
17.1
通讯作者：
Chang C
中科院分区：
文献类型：
--
作者：
Wu MH;Ma WL;Hsu CL;Chen YL;Ou JH;Ryan CK;Hung YC;Yeh S;Chang C
B型肝炎病毒（HBV）诱导的肝炎和致癌物诱导的肝细胞癌（HCC）与血清雄激素浓度相关。然而，雄激素或雄激素受体（AR）如何促进HBV诱导的肝癌发生仍不清楚。我们发现，肝AR促进HBV诱导的肝癌发生在HBV转基因小鼠中，这些小鼠仅在肝细胞中缺乏AR（HBV-L-AR−/y）。接受低剂量致癌物N′-N′-二乙基亚硝胺（DEN）的HBV-L-AR−/y小鼠与野生型HBV-AR+/y同窝小鼠相比，HCC的发生率较低，肿瘤大小较小，病灶形成较少，甲胎蛋白HCC标志物较少。我们发现肝AR通过直接结合到病毒核心启动子附近的雄激素反应元件来增强HBV RNA转录，从而增加HBV病毒滴度。该活性与其下游靶基因HBx蛋白协同作用形成正反馈机制，促进肝癌发生。施用选择性降解AR的化合物ASC-J 9能够抑制DEN-HBV-AR+/y小鼠中的HCC肿瘤大小。这些结果表明，靶向AR，而不是雄激素，可以作为一种新的治疗方法来对抗HBV诱导的HCC。
Hepatitis B virus (HBV)–induced hepatitis and carcinogen-induced hepatocellular carcinoma (HCC) are associated with serum androgen concentration. However, how androgen or the androgen receptor (AR) contributes to HBV-induced hepatocarcinogenesis remains unclear. We found that hepatic AR promotes HBV-induced hepatocarcinogenesis in HBV transgenic mice that lack AR only in the liver hepatocytes (HBV-L-AR−/y). HBV-L-AR−/y mice that received a low dose of the carcinogen N′-N′-diethylnitrosamine (DEN) have a lower incidence of HCC and present with smaller tumor sizes, fewer foci formations, and less α-fetoprotein HCC marker than do their wild-type HBV-AR+/y littermates. We found that hepatic AR increases the HBV viral titer by enhancing HBV RNA transcription through direct binding to the androgen response element near the viral core promoter. This activity forms a positive feedback mechanism with cooperation with its downstream target gene HBx protein to promote hepatocarcinogenesis. Administration of a chemical compound that selectively degrades AR, ASC-J9, was able to suppress HCC tumor size in DEN-HBV-AR+/y mice. These results demonstrate that targeting the AR, rather than the androgen, could be developed as a new therapy to battle HBV-induced HCC.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
13.5
作者：
Ming, L;Thorgeirsson, SS;Sun, ZT
通讯作者：
Sun, ZT
DOI：
10.1111/j.1440-1746.1997.tb00513.x
发表时间：
1997-10-01
影响因子：
4.1
作者：
Chen, CJ;Yu, MW;Liaw, YF
通讯作者：
Liaw, YF
DOI：
10.1111/j.1749-6632.2009.03704.x
发表时间：
2009-01-01
期刊：
STEROID ENZYMES AND CANCER
影响因子：
--
作者：
Berasain, C.;Castillo, J.;Avila, M. A.
通讯作者：
Avila, M. A.
影响因子：
13.5
作者：
SHIRATORI, Y;SHIINA, S;OMATA, M
通讯作者：
OMATA, M