Androgen/androgen receptor axis maintains and promotes cancer cell stemness through direct activation of Nanog transcription in hepatocellular carcinoma.
Androgen/androgen receptor axis maintains and promotes cancer cell stemness through direct activation of Nanog transcription in hepatocellular carcinoma.
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雄激素/雄激素受体轴通过直接激活肝细胞癌中的nanog转录来维持和促进癌细胞干性
DOI：
10.18632/oncotarget.9192
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发表时间：
2016-06-14
期刊：
影响因子：
--
通讯作者：
Liang Z
中科院分区：
文献类型：
--
作者：
Jiang L;Shan J;Shen J;Wang Y;Yan P;Liu L;Zhao W;Xu Y;Zhu W;Su L;Chen J;Cheng F;Yao H;Xu H;Qian C;Liang Z
肝细胞癌是最常见的恶性肿瘤之一。由于男性是这场灾难的主要受害者，肝癌的发病率具有很强的性别二型性。虽然一些研究已经发现雄激素/雄激素受体(AR)轴与肝癌发病之间的典型相关性，但其机制仍很大程度上是未知的。肿瘤干细胞(CSCs)是导致多种肿瘤恶性行为的一小部分癌细胞，在包括肝癌在内的多种肿瘤的发生发展中起着重要作用。然而，雄激素/AR轴是否参与了对肝癌细胞干性的调节仍不清楚。我们先前的研究已经证实，多能因子Nanog不仅是一个干性生物标志物，而且是肝细胞癌中CSCs的有效调节因子。在这项研究中，我们揭示了雄激素/AR轴可以通过直接与其启动子结合而转录激活Nanog表达来促进肝癌细胞的干性。在肝细胞癌组织中，我们发现AR的表达异常高，并与Nanog相关。然后，通过CRISPR/Cas9系统用绿色荧光蛋白(GFP)标记细胞内源性Nanog，验证了AR和Nanog在肝癌细胞中的共存。通过体外实验，我们证明了AXIS可以促进肝癌细胞的干化，这种作用是以Nanog依赖的方式并通过激活其转录来实现的。移植瘤实验证实了AXIS在体内促进肿瘤形成的作用。总之，我们对雄激素/AR轴在肝细胞癌中的作用有了新的认识，并为抑制该轴在肝细胞癌治疗中的作用提供了一个潜在的途径。
Hepatocellular carcinoma (HCC) is one of the most common and malignant cancers. The HCC incidence gets a strong sexual dimorphism as men are the major sufferers in this disaster. Although several studies have uncovered the presentative correlation between the axis of androgen/androgen receptor (AR) and HCC incidence, the mechanism is still largely unknown. Cancer stem cells (CSCs) are a small subgroup of cancer cells contributing to multiple tumors malignant behaviors, which play an important role in oncogenesis of various cancers including HCC. However, whether androgen/AR axis involves in regulation of HCC cells stemness remains unclear. Our previous study had identified that the pluripotency factor Nanog is not only a stemness biomarker, but also a potent regulator of CSCs in HCC. In this study, we revealed androgen/AR axis can promote HCC cells stemness by transcriptional activation of Nanog expression through directly binding to its promoter. In HCC tissues, we found that AR expression was abnormal high and got correlation with Nanog. Then, by labeling cellular endogenous Nanog with green fluorescent protein (GFP) through CRISPR/Cas9 system, it verified the co-localization of AR and Nanog in HCC cells. With in vitro experiments, we demonstrated the axis can promote HCC cells stemness, which effect is in a Nanog-dependent manner and through activating its transcription. And the xenografted tumor experiments confirmed the axis effect on tumorigenesis facilitation in vivo. Above all, we revealed a new sight of androgen/AR axis roles in HCC and provided a potential way for suppressing the axis in HCC therapy.
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影响因子：
64.5
作者：
Li Z;Tuteja G;Schug J;Kaestner KH
通讯作者：
Kaestner KH
影响因子：
--
作者：
O'Neill D;Jones D;Wade M;Grey J;Nakjang S;Guo W;Cork D;Davies BR;Wedge SR;Robson CN;Gaughan L
通讯作者：
Gaughan L
影响因子：
45.3
作者：
Grimaldi, C;Bleiberg, H;Wils, J
通讯作者：
Wils, J
影响因子：
4.8
作者：
Lin, Tzu-Hua;Lee, Soo Ok;Chang, Chawnshang
通讯作者：
Chang, Chawnshang
影响因子：
2.6
作者：
Li Jialiang;Chen Feng;Liu DePei
通讯作者：
Liu DePei