Division of Gastroenterology & Hepatology, Department of Medicine, Stanford University, Stanford, California, USA.
Prostate. 2013 May;73(6):582-9. doi: 10.1002/pros.22598. Epub 2012 Oct 11.
Neuroendocrine (NE) prostate tumors and neuroendocrine differentiation (NED) in prostatic adenocarcinomas have been associated with poor prognosis. In this study, we used the TRAMP mouse model that develops NE prostate tumors to identify key factors that can lead to NED. We have previously reported that NE tumors express the forkhead transcription factor, Foxa2, Mash1 (mouse achaete scute homolog-1), as well as Synaptophysin. In TRAMP, the prostatic intraepithelial neoplasia (PIN) first expresses Foxa2 and Synaptophysin, which then progresses to NE cancer. In order to determine if Foxa2 is dispensable for development or maintenance of NE cancer, a conditional knock-out of Foxa2 in TRAMP mice was generated by breeding mice with two floxed alleles of Foxa2 and one copy of Nkx3.1-Cre. Nkx3.1-Cre/Foxa2(loxP/loxP) mice showed loss of Foxa2 expression in embryonic prostatic buds. No expression of Foxa2 was seen in the adult prostate in either conditional null or control mice. Foxa2 is universally expressed in all wild type TRAMP NE tumors, but Mash1 expression is seen only in a few samples in a few cells. With the loss of Foxa2 in the NE tumors of the TRAMP/Nkx3.1-Cre/Foxa2(loxP/loxP) mice, the expression of the pro-neuronal gene Mash1 is upregulated. NE tumors from both the TRAMP control and Foxa2-deficient TRAMP prostate express Synaptophysin and SV40 Large T-antigen, and both show a loss of androgen receptor expression in NE cells. These studies suggest that the TRAMP NE tumors can form in the absence of Foxa2 by an up regulation of Mash1.
神经内分泌（NE）前列腺肿瘤和前列腺腺癌中的神经内分泌分化（NED）与预后不良有关。在这项研究中，我们使用了会发展出 NE 前列腺肿瘤的 TRAMP 小鼠模型，以确定可能导致 NED 的关键因素。我们之前曾报道过，NE 肿瘤表达叉头转录因子 Foxa2、Mash1（小鼠 achaete scute 同源物-1）以及突触素。在 TRAMP 中，前列腺上皮内瘤变（PIN）首先表达 Foxa2 和突触素，然后进展为 NE 癌。为了确定 Foxa2 是否对于 NE 癌的发生或维持是可有可无的，我们通过繁殖具有两个 Foxa2 基因 floxed 等位基因和一个 Nkx3.1-Cre 基因拷贝的小鼠，生成了 Foxa2 在 TRAMP 小鼠中的条件性敲除。Nkx3.1-Cre/Foxa2(loxP/loxP) 小鼠在胚胎前列腺芽中表现出 Foxa2 表达缺失。在条件性敲除或对照小鼠的成年前列腺中均未观察到 Foxa2 的表达。Foxa2 在所有野生型 TRAMP NE 肿瘤中均普遍表达，但 Mash1 表达仅在少数样本中的少数细胞中可见。在 TRAMP/Nkx3.1-Cre/Foxa2(loxP/loxP) 小鼠的 NE 肿瘤中 Foxa2 缺失后，前神经元基因 Mash1 的表达上调。来自 TRAMP 对照和 Foxa2 缺陷型 TRAMP 前列腺的 NE 肿瘤均表达突触素和 SV40 大 T 抗原，并且在 NE 细胞中均表现出雄激素受体表达缺失。这些研究表明，在缺乏 Foxa2 的情况下，TRAMP NE 肿瘤可以通过 Mash1 的上调形成。
