Androgen Receptor (AR)-TLR4 Crosstalk Mediates Gender Disparities in Hepatocellular Carcinoma Incidence and Progression
Androgen Receptor (AR)-TLR4 Crosstalk Mediates Gender Disparities in Hepatocellular Carcinoma Incidence and Progression
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DOI：
10.7150/jca.30682
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发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Han, Qiuju;Yang, Dan;Zhang, Jian
背景：雄激素受体（AR）在调节肝细胞癌（HCC）的恶性肿瘤和性别差异中发挥作用。方法：采用DEN/CCL 4诱导小鼠肝癌模型，检测小鼠肝癌发生情况，采用qPCR和流式细胞仪检测肝组织中TLR 4和AR信号。体外观察TLR 4激动剂LPS和/或雄激素DHT对肝癌细胞增殖、集落形成和迁移的影响。结果：雄性小鼠比雌性小鼠更易发生肝癌，AR与TLR 4的表达有相关性。同时，我们发现雄性小鼠的基线TLR 4水平高于雌性小鼠。DEN/CCL 4处理可增加雄性小鼠的AR表达。AR在人肝癌细胞系中呈组成型表达。双氢睾酮（DHT）刺激HepG 2和HepG 2 2.15细胞中TLR 4的表达，这可以通过沉默AR来阻断。另一方面，用LPS处理刺激AR表达，但它被TLR 4拮抗剂和TLR 4缺陷细胞阻断。DHT处理加剧了TLR 4诱导的HepG 2细胞增殖、集落形成、迁移和侵袭。AR和TLR 4之间的正相关关系在人类HCC samples.Conclusions：DHT-AR-TLR 4信号增强HCC细胞的发展，并促进其迁移和侵袭，证明了HCC的性别差异的机制。
Background: Androgen receptor (AR) has a role in regulating malignancies and gender disparities in hepatocellular carcinoma (HCC). Recently, TLR4 activation is demonstrated to be required for HCC progression; however, whether and how TLR4 interacts with AR is largely unknown.Methods: The tumorigenesis was detected in female and male mice induced by DEN/CCL4, then TLR4 and AR signals were detected in liver tissues by qPCR and FACS. The proliferation, colony formation and migration of HCC cell treated with TLR4 agonist LPS, or/and androgen DHT were evaluated in vitro. Furthermore, the expression of TLR4 and AR was detected by IHC in tissue microarray of HCC, and correlation of AR and TLR4 was defined.Results: Male mice are more susceptible to develop HCC than female mice. Meanwhile, we found baseline TLR4 levels were higher in male mice than in female mice. AR expression in male mice was increased by treatment with DEN/CCL4. And, AR was constitutively expressed in human HCC cell lines. Dihydrotestosterone (DHT) stimulated TLR4 expression in both HepG2 and HepG2 2.15 cells, which could be blocked by silencing AR. On the other hand, treatment with LPS stimulated AR expression, but it was blocked by treatment with TLR4 antagonist and in cells deficient for TLR4. DHT treatment exacerbated TLR4-induced cellular proliferation, colony formation, migration, and invasion of HepG2 cells. The positive relationship between AR and TLR4 was confirmed in human HCC samples.Conclusions: DHT-AR-TLR4 signaling enhances the development of HCC cells and facilitates their migration and invasion, demonstrating a mechanism underlying gender disparity in HCC.