早期的报告提示，雄激素/雄激素受体（AR）信号促进肝癌发展，然而，所有针对中晚期肝细胞癌（HCC）的抗雄激素临床试验的失败都没有合理解释。这项研究中，我们在肝细胞转移癌中检测雄激素受体的功能。将由致癌物诱导形成的肝癌小鼠模型中敲除肝细胞雄激素受体和未敲除受体的野生型进行比较，来判断肝脏雄激素受体在肝细胞转移癌中的作用。我们也研究肿瘤组织学，肿瘤转移的风险，体内的肿瘤细胞存活率，以及细胞失巢凋亡和体外培养时所应用的原发性肝脏肿瘤细胞的迁移情况。我们还研究了雄激素受体表达联合分子靶向药物索拉非尼在肝癌转移小鼠模型中的治疗潜力。我们找到了一种新的癌症表型，即缺乏肝雄激素受体的小鼠可能会出现更多种未分化肿瘤，而且在出现转移时，肿瘤的体积更大。这些小鼠也可能因为肺部转移癌而更早死去，这说明肝脏雄激素受体发挥着双重且相反的作用，促进肝癌的发生却抑制肝癌的转移。解剖发现肝雄激素受体通过分别抑制p38的磷酸化/活化和核因子kappa B（NF-kB）/metallopeptidase9（MMP9）途径，可以增强失巢凋亡和抑制肝癌细胞迁移。此外，从体内临床前试验推断出，一项具有增加雄激素受体表达并减少多激酶抑制剂的联合治疗药物（索拉菲尼）表现出较好的疗效。结论：我们的研究表明，雄激素受体可以协调肝内信号层次和细胞行为，从而影响肝癌的进展。联合治疗的结果为对肝癌转移阶段开发新治疗提供范例。


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 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 a 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 the molecular targeting agent sorafenib in an 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 the metastatic stage. These mice also died earlier with increased lung metastasis, suggesting that 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 by way of suppression of p38 phosphorylation/activation and the nuclear factor kappa B (NF-κB)/matrix metallopeptidase 9 (MMP9) pathway, respectively. In addition, the in vivo preclinical trials concluded that a combination therapy of increased AR expression and reduced multiple-kinase inhibitor (sorafenib) exhibited better therapeutic efficacy. Conclusion: Our study demonstrates that AR could orchestrate intrahepatic signaling hierarchies and cellular behaviors, consequently affect HCC progression. Results from combination therapy shed light on developing new therapeutic paradigms for battling HCC at later metastatic stages.

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