Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis.
Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis.
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肝雄激素受体通过调节细胞迁移和厌氧菌来抑制肝细胞癌转移。
DOI：
10.1002/hep.25644
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发表时间：
2012-07
期刊：
影响因子：
13.5
通讯作者：
Chang, Chawnshang
中科院分区：
文献类型：
--
作者：
Ma, Wen-Lung;Hsu, Cheng-Lung;Yeh, Chun-Chieh;Wu, Ming-Heng;Huang, Chiung-Kuei;Jeng, Long-Bin;Hung, Yao-Ching;Lin, Tze-Yi;Yeh, Shuyuan;Chang, Chawnshang
早期的研究表明雄激素/雄激素受体（AR）信号促进肝癌的发生。然而，所有抗雄激素临床试验在晚期肝细胞癌（HCC）中均失败，且没有合理的解释。在这项研究中，我们研究了HCC癌转移中的AR功能。我们通过在致癌物诱导的HCC小鼠模型中比较肝细胞AR敲除和野生型，研究了肝AR在HCC转移中的作用。我们研究了肿瘤组织学，癌症转移的风险，在体内的癌症生存，以及细胞失巢凋亡和迁移使用原代肝肿瘤体外培养。我们还研究了AR表达与分子靶向剂索拉非尼组合在HCC转移小鼠模型中的治疗潜力。我们发现了一种新的癌症表型，其中缺乏肝脏AR的小鼠在晚期转移阶段发展出更多的未分化肿瘤和更大的肿瘤大小。这些小鼠也较早死亡，肺转移增加，表明肝AR可能发挥双重但相反的作用，促进HCC的启动，但抑制HCC转移。机械解剖发现肝AR可分别通过抑制p38磷酸化/激活和NFκ B-MMP 9通路增强HCC细胞的失巢凋亡和抑制HCC细胞的迁移。此外，体内临床前试验得出结论，增加AR表达和减少多激酶抑制剂（索拉非尼）的联合治疗显示出更好的治疗效果。我们的研究表明，AR可以协调肝内信号传导和细胞行为，从而影响HCC的进展。联合治疗的结果为开发新的治疗模式以对抗晚期转移性肝癌提供了启示。
Early reports suggested androgen/androgen receptor (AR) signals promote hepatocarcinogenesis. However, all antiandrogen clinical trials failed in advanced hepatocellular carcinoma (HCC) without reasonable explanations. We have examined AR functions in HCC cancer metastasis in this study. We examined hepatic AR roles in HCC metastasis by comparing liver hepatocyte AR knockout and wildtype in carcinogen-induced HCC mouse model. We examined tumor histology, cancer metastatic risks, and cancer survival in vivo, as well as cell anoikis and migration using primary hepatic tumor culture in vitro. We also examined therapeutic potentials of AR expression combined with molecular targeting agent, Sorafenib, in HCC metastasis mouse model. We found a novel cancer phenotype in which mice lacking hepatic AR developed more undifferentiated tumors and larger tumor size at later metastatic stage. These mice also died earlier with increased lung metastasis, suggesting hepatic-AR may play dual yet opposite roles to promote HCC initiation but suppress HCC metastasis. Mechanistic dissection found that hepatic AR could enhance anoikis and suppress migration of HCC cells via suppression of p38 phosphorylation/activation and the NFκB-MMP9 pathway, respectively. In addition, the in vivo pre-clinical trials concluded that a combination therapy of increased AR expression and reduced multiple-kinase inhibitor (Sorafenib) exhibited better therapeutic efficacy. Our study demonstrated that AR could orchestrate intrahepatic signalling hierarchies and cellular behavior, consequently affect HCC progression. Results from combination therapy shed a light on developing new therapeutic paradigm for battling HCC at later metastatic stage.
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影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
2.1
作者：
Boorjian, S;Ugras, S;Scherr, DS
通讯作者：
Scherr, DS
影响因子：
9.6
作者：
NAGASUE, N;YU, L;NAKAMURA, T
通讯作者：
NAKAMURA, T
影响因子：
2.9
作者：
GUPTA, S;KORULA, J
通讯作者：
KORULA, J
影响因子：
51.1
作者：
Je, Youjin;Schutz, Fabio A. B.;Choueiri, Toni K.
通讯作者：
Choueiri, Toni K.