State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an Shaanxi Province, P.R. China; Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan Hubei Province, P.R. China.
Hepatology. 2014 Mar;59(3):958-73. doi: 10.1002/hep.26735. Epub 2014 Feb 6.
UNLABELLED: Forkhead box Q1 (FoxQ1) is a master regulator of tumor metastasis. However, the molecular mechanism of FoxQ1 in regulating hepatocellular carcinoma (HCC) metastasis remains unknown. Here we report a novel function for FoxQ1 in modifying the tumor microenvironment to promote HCC metastasis. FoxQ1 expression was an independent and significant risk factor for the recurrence and survival in two independent cohorts totaling 1,002 HCC patients. FoxQ1 induced epithelial-mesenchymal transition (EMT) through the transactivation of ZEB2 expression by directly binding to the ZEB2 promoter. Knockdown of ZEB2 decreased FoxQ1-enhanced HCC metastasis, whereas up-regulation of ZEB2 rescued the decreased metastasis induced by FoxQ1 knocking down. Additionally, serial deletion, site-directed mutagenesis, and a chromatin immunoprecipitation assays showed that VersicanV1, which promoted HCC metastasis and macrophage attraction, was a direct transcriptional target of FoxQ1. FoxQ1-induced VersicanV1 expression promoted the secretion of chemokine (C-C motif) ligand 2 (CCL2) from HCC cells. Chemotaxis assay showed that the culture media from FoxQ1-overexpressing HCC cells increased the migratory activity of the macrophages. Inhibition of VersicanV1 and CCL2 expression significantly inhibited FoxQ1-mediated macrophage migration. In animal studies, the up-regulation of FoxQ1 in HCC cells promoted HCC metastasis and intratumoral tumor associated macrophage (TAM) infiltration, whereas knockdown of VersicanV1 reduced FoxQ1-mediated HCC metastasis and intratumoral TAM infiltration. Depletion of macrophages using clodronate liposomes dramatically decreased FoxQ1-enhanced HCC metastasis. In human HCC tissues, FoxQ1 expression was positively correlated with ZEB2 and VersicanV1 expression and intratumoral TAM infiltration. Patients with positive coexpression of FoxQ1 and ZEB2, FoxQ1, and VersicanV1, or FoxQ1 and intratumoral TAMs were associated with poorer prognosis. CONCLUSION: FoxQ1 promotes HCC metastasis by transactivating ZEB2 and VersicanV1 expression, resulting in the induction of EMT and the recruitment of macrophage infiltration.
未加标签：叉头框 Q1（FoxQ1）是肿瘤转移的主调控因子。然而，FoxQ1 调节肝细胞癌（HCC）转移的分子机制尚不清楚。在这里，我们报告了 FoxQ1 在修饰肿瘤微环境以促进 HCC 转移方面的新功能。FoxQ1 的表达是两个独立的 HCC 患者队列中 1002 例患者的复发和生存的独立且显著的危险因素。FoxQ1 通过直接结合 ZEB2 启动子转录激活 ZEB2 表达诱导上皮-间充质转化（EMT）。敲低 ZEB2 可降低 FoxQ1 增强的 HCC 转移，而上调 ZEB2 可挽救 FoxQ1 敲低引起的转移减少。此外，连续缺失、定点突变和染色质免疫沉淀测定表明，促进 HCC 转移和巨噬细胞吸引的 VersicanV1 是 FoxQ1 的直接转录靶标。FoxQ1 诱导的 VersicanV1 表达促进 HCC 细胞中趋化因子（C-C 基序）配体 2（CCL2）的分泌。趋化性测定表明，FoxQ1 过表达 HCC 细胞的培养物增加了巨噬细胞的迁移活性。在动物研究中，上调 HCC 细胞中的 FoxQ1 促进 HCC 转移和肿瘤内肿瘤相关巨噬细胞（TAM）浸润，而下调 VersicanV1 则减少 FoxQ1 介导的 HCC 转移和肿瘤内 TAM 浸润。使用氯膦酸盐脂质体耗尽巨噬细胞可显著降低 FoxQ1 增强的 HCC 转移。在人类 HCC 组织中，FoxQ1 表达与 ZEB2 和 VersicanV1 表达以及肿瘤内 TAM 浸润呈正相关。FoxQ1 和 ZEB2、FoxQ1 和 VersicanV1 或 FoxQ1 和肿瘤内 TAMs 共表达阳性的患者预后较差。 结论：FoxQ1 通过转录激活 ZEB2 和 VersicanV1 的表达促进 HCC 转移，从而诱导 EMT 并募集巨噬细胞浸润。
Biochem Biophys Res Commun. 2015-7-31
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