Aryl hydrocarbon receptor promotes hepatocellular carcinoma tumorigenesis by targeting intestine-specific homeobox expression
Aryl hydrocarbon receptor promotes hepatocellular carcinoma tumorigenesis by targeting intestine-specific homeobox expression
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DOI：
10.1002/mc.22658
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发表时间：
2017-10-01
影响因子：
4.6
通讯作者：
Wang, Shen-Nien
中科院分区：
文献类型：
--
作者：
Hsu, Shih-Hsien;Wang, Li-Ting;Wang, Shen-Nien
芳烃受体（AHR）是一种主要的化学传感器，被认为在各种生物环境中发挥作用，包括细胞周期调节和肿瘤发生。然而，其监管机制仍不清楚。我们在此提出了一种新机制，AHR 通过靶向肝细胞癌 (HCC) 中癌基因肠特异性同源盒 (ISX) 的表达来促进肿瘤发生。与配对的肿瘤邻近组织和非 HCC 肿瘤相比，HCC 表现出 AHR 表达增加和分层模式。与低表达和中等表达的患者相比，AHR 高表达的患者的生存期明显较短。在功能上，AHR被发现以新发现的原癌基因ISX为目标，导致该基因及其下游靶标CCND1和E2F1的表达增加。肝癌细胞中 AHR 或 ISX 的消除抑制了细胞生长，而过度表达则促进细胞增殖并导致体外和体内致瘤活性增强。这些结果提供了证据支持 AHR/ISX 轴在 HCC 肿瘤发生中的关键作用，并表明其作为 HCC 新的治疗和预后靶点的潜在用途。
The aryl hydrocarbon receptor (AHR), a major chemical sensor, is thought to play a role in various biological contexts, including cell cycle regulation and tumorigenesis. However, its regulatory mechanisms remain unclear. We propose herein a novel mechanism through which AHR promotes tumorigenesis by targeting expression of the oncogene intestine-specific homeobox (ISX) in hepatocellular carcinoma (HCC). Compared to paired tumor-adjacent tissues and non-HCC tumors, HCCs exhibited an increased and hierarchical pattern of AHR expression. Patients exhibiting high AHR expression had a significantly shorter survival duration, compared to those with low and medium expression. Functionally, AHR was found to target the newly discovered proto-oncogene, ISX, resulting in the increased expression of this gene and its downstream targets, CCND1 and E2F1. Ablation of AHR or ISX in hepatoma cells suppressed cell growth, whereas overexpression promoted cell proliferation and led to enhanced tumorigenic activity in vitro and in vivo. These results provide evidence to support a critical role for the AHR/ISX axis in HCC tumorigenesis and suggest its potential utility as a new therapeutic and prognostic target for HCC.