Androgen receptor-independent function of FoxA1 in prostate cancer metastasis.
Androgen receptor-independent function of FoxA1 in prostate cancer metastasis.
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DOI：
10.1158/0008-5472.can-12-3468
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发表时间：
2013-06-15
期刊：
影响因子：
11.2
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Jin HJ;Zhao JC;Ogden I;Bergan RC;Yu J
FoxA 1（FOXA 1）是雄激素受体（AR）的一个开创性转录因子，其对于前列腺的谱系特异性基因表达是不可或缺的。迄今为止，关于FoxA 1在前列腺癌进展和预后中的作用的报道相互矛盾。随着最近在人类前列腺肿瘤中发现复发性FoxA 1突变，全面了解FoxA 1功能变得非常重要。在这里，通过基因组分析，我们揭示了FoxA 1通过不同的机制调节两个不同的致癌过程。FoxA 1诱导需要AR途径的细胞生长。另一方面，FoxA 1通过AR非依赖性机制直接对抗AR信号传导的作用来抑制细胞运动和上皮-间质转化（EMT）。使用原位小鼠模型，我们进一步表明，FoxA 1抑制体内前列腺肿瘤转移。与这些对肿瘤进展的矛盾作用一致，FoxA 1表达在以细胞增殖为主要特征的局限性前列腺癌中略微上调，但当疾病进展到细胞运动性和EMT至关重要的转移阶段时显著下调。重要的是，最近鉴定的FoxA 1突变体在抑制细胞运动方面的能力大大减弱。综上所述，我们的研究结果说明了FoxA 1作为转移抑制剂的AR独立功能，并提供了一种机制，通过这种机制，复发性FoxA 1突变有助于前列腺癌的进展。
FoxA1 (FOXA1) is a pioneering transcription factor of the androgen receptor (AR) that is indispensible for the lineage-specific gene expression of the prostate. To date, there have been conflicting reports on the role of FoxA1 in prostate cancer progression and prognosis. With recent discoveries of recurrent FoxA1 mutations in human prostate tumors, comprehensive understanding of FoxA1 function has become very important. Here, through genomic analysis we reveal that FoxA1 regulates two distinct oncogenic processes via disparate mechanisms. FoxA1 induces cell growth requiring the AR pathway. On the other hand, FoxA1 inhibits cell motility and epithelial-to-mesenchymal transition (EMT) through AR-independent mechanism directly opposing the action of AR signaling. Using orthotopic mouse models we further show that FoxA1 inhibits prostate tumor metastasis in vivo. Concordant with these contradictory effects on tumor progression, FoxA1 expression is slightly up-regulated in localized prostate cancer wherein cell proliferation is the main feature, but is remarkably down-regulated when the disease progresses to metastatic stage for which cell motility and EMT are essential. Importantly, recently identified FoxA1 mutants have drastically attenuated ability in suppressing cell motility. Taken together, our findings illustrate an AR-independent function of FoxA1 as a metastasis inhibitor and provide a mechanism by which recurrent FoxA1 mutations contribute to prostate cancer progression.