Transcription factor AP-4 promotes tumorigenic capability and activates the Wnt/β-catenin pathway in hepatocellular carcinoma.
Transcription factor AP-4 promotes tumorigenic capability and activates the Wnt/β-catenin pathway in hepatocellular carcinoma.
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转录因子 AP-4 促进肝细胞癌的致瘤能力并激活 Wnt/β-catenin 通路
作者：
Song J;Xie C;Jiang L;Wu G;Zhu J;Zhang S;Tang M;Song L;Li J
据报道，转录因子激活增强子结合蛋白4（TFAP 4）上调，并与几种癌症的侵袭性表型。然而，TFAP 4致癌作用的确切机制在很大程度上仍然未知。研究方法：采用实时荧光定量PCR（qPCR）和免疫组化（IHC）检测肝癌细胞和组织中TFAP 4的表达水平。进行体外和体内测定以研究TFAP 4在肿瘤起始细胞（TIC）样表型中的致癌功能和HCC细胞的致瘤能力。进行荧光素酶报告基因和染色质免疫沉淀（ChIP）-qPCR测定，以确定TFAP 4介导的HCC侵袭性的潜在机制。结果如下：TFAP 4在人HCC中显著上调，并且与HCC患者的总体和无复发生存率显著较差相关。此外，我们发现TFAP 4的过表达显著增强，而沉默TFAP 4抑制，肿瘤球形成能力和侧群细胞在肝癌细胞中的比例在体外，和异位TFAP 4增强肝癌细胞在体内的致瘤性。从机制上讲，我们证明了TFAP 4通过直接结合DVL 1（凌乱片段极性蛋白1）和LEF 1（淋巴增强子结合因子1）的启动子在激活Wnt/β-连环蛋白信号传导中发挥重要作用。结论：我们的研究结果为HCC中Wnt/β-catenin通路过度活化的潜在机制以及TFAP 4增强HCC细胞肿瘤形成能力的致癌能力提供了新的见解。
It has been reported that the transcription factor activating enhancer-binding protein 4 (TFAP4) is upregulated and associated with an aggressive phenotype in several cancers. However, the precise mechanisms underlying the oncogenic role of TFAP4 remain largely unknown. Methods: TFAP4 expression levels in hepatocellular carcinoma (HCC) cells and tissues were detected by quantitative real-time PCR (qPCR) and immunohistochemistry (IHC). In vitro and in vivo assays were performed to investigate the oncogenic function of TFAP4 in the tumor-initiating cell (TIC)-like phenotype and the tumorigenic capability of HCC cells. Luciferase reporter and chromatin immunoprecipitation (ChIP)-qPCR assays were performed to determine the underlying mechanism of TFAP4-mediated HCC aggressiveness. Results: TFAP4 was markedly upregulated in human HCC, and was associated with significantly poorer overall and relapse-free survival in patients with HCC. Furthermore, we found that overexpression of TFAP4 significantly enhanced, whereas silencing TFAP4 inhibited, the tumor sphere formation ability and proportion of side-population cells in HCC cells in vitro, and ectopic TFAP4 enhanced the tumorigenicity of HCC cells in vivo. Mechanistically, we demonstrated that TFAP4 played an important role in activating Wnt/β-catenin signaling by directly binding to the promoters of DVL1 (dishevelled segment polarity protein 1) and LEF1 (lymphoid enhancer binding factor 1). Conclusions: Our results provide new insight into the mechanisms underlying hyperactivation of the Wnt/β-catenin pathway in HCC, as well the oncogenic ability of TFAP4 to enhance the tumor-forming ability of HCC cells.
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作者：
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