Foxm1 Expression in Prostate Epithelial Cells Is Essential for Prostate Carcinogenesis
Foxm1 Expression in Prostate Epithelial Cells Is Essential for Prostate Carcinogenesis
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DOI：
10.1074/jbc.m113.455089
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发表时间：
2013-08-02
影响因子：
4.8
通讯作者：
Kalin, Tanya V.
中科院分区：
文献类型：
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作者：
Cai, Yuqi;Balli, David;Kalin, Tanya V.
晚期前列腺癌（PCa）的治疗仍然是一个挑战。鉴定调节PCa起始和进展的新分子机制将为开发新的癌症治疗提供靶点。Foxm 1转录因子在肿瘤细胞、炎症细胞和肿瘤微环境细胞中高度上调。然而，其在PCa病变的不同细胞群中的功能尚不清楚。为了确定Foxm 1在前列腺癌发展过程中肿瘤细胞中的作用，我们产生了两种新型转基因小鼠模型，一种表现出Foxm 1功能获得，另一种表现出Foxm 1功能丧失，在前列腺上皮特异性Probasin启动子的控制下。在使用SV 40大T抗原诱导PCa的转基因腺癌小鼠前列腺（TRAMP）模型中，Foxm 1的缺失降低了肿瘤的生长和转移。前列腺肿瘤发生减少与肿瘤细胞增殖减少以及细胞增殖和肿瘤转移关键基因（包括Cdc 25 b、细胞周期蛋白B1、Plk-1、Lox和Versican）下调相关。此外，肿瘤相关的血管生成减少，与Vegf-A表达减少一致。11 β-Hsd 2是一种在肿瘤细胞增殖中起重要作用的酶，其mRNA和蛋白水平在体内Foxm 1缺陷的PCa肿瘤和体外Foxm 1缺失的TRAMP C2细胞中下调。Foxm 1通过-892/-879区域与小鼠11 β-Hsd 2启动子结合并增加其转录活性，表明11 β-Hsd 2是Foxm 1的直接转录靶标。在没有TRAMP的情况下，Foxm 1单独过表达或与p19（ARF）肿瘤抑制因子的抑制相结合引起了强烈的上皮增生，但不足以诱导从增生到PCa的进展。Foxm 1在前列腺上皮细胞中的表达是前列腺癌发生的关键，这表明抑制Foxm 1是前列腺癌化疗的一种有前途的治疗方法。
The treatment of advanced prostate cancer (PCa) remains a challenge. Identification of new molecular mechanisms that regulate PCa initiation and progression would provide targets for the development of new cancer treatments. The Foxm1 transcription factor is highly up-regulated in tumor cells, inflammatory cells, and cells of tumor microenvironment. However, its functions in different cell populations of PCa lesions are unknown. To determine the role of Foxm1 in tumor cells during PCa development, we generated two novel transgenic mouse models, one exhibiting Foxm1 gain-of-function and one exhibiting Foxm1 loss-of-function under control of the prostate epithelial-specific Probasin promoter. In the transgenic adenocarcinoma mouse prostate (TRAMP) model of PCa that uses SV40 large T antigen to induce PCa, loss of Foxm1 decreased tumor growth and metastasis. Decreased prostate tumorigenesis was associated with a decrease in tumor cell proliferation and the down-regulation of genes critical for cell proliferation and tumor metastasis, including Cdc25b, Cyclin B1, Plk-1, Lox, and Versican. In addition, tumor-associated angiogenesis was decreased, coinciding with reduced Vegf-A expression. The mRNA and protein levels of 11 beta-Hsd2, an enzyme playing an important role in tumor cell proliferation, were down-regulated in Foxm1-deficient PCa tumors in vivo and in Foxm1-depleted TRAMP C2 cells in vitro. Foxm1 bound to, and increased transcriptional activity of, the mouse 11 beta-Hsd2 promoter through the -892/-879 region, indicating that 11 beta-Hsd2 was a direct transcriptional target of Foxm1. Without TRAMP, overexpression of Foxm1 either alone or in combination with inhibition of a p19(ARF) tumor suppressor caused a robust epithelial hyperplasia, but was insufficient to induce progression from hyperplasia to PCa. Foxm1 expression in prostate epithelial cells is critical for prostate carcinogenesis, suggesting that inhibition of Foxm1 is a promising therapeutic approach for prostate cancer chemotherapy.