Loss of JUNB/AP-1 promotes invasive prostate cancer
Loss of JUNB/AP-1 promotes invasive prostate cancer
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DOI：
10.1038/cdd.2014.213
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发表时间：
2015-04-01
影响因子：
12.4
通讯作者：
Wagner, E. F.
中科院分区：
文献类型：
--
作者：
Thomsen, M. K.;Bakiri, L.;Wagner, E. F.
前列腺癌是西方世界男性死亡的常见原因。相对较少的遗传变异已被确定，可能是由于疾病的异质性。在这里，我们发现转录因子JUNB/AP-1限制了前列腺癌的进展。与正常人前列腺相比，JUNB表达在低级别前列腺癌中增加，但在高级别样品中下调，并在所有转移性样品中进一步降低。为了模拟这种下调在功能上具有重要意义的假设，我们在小鼠前列腺上皮中遗传灭活了Junb。当与Pten（磷酸酶和张力蛋白同源物）丢失相结合时，双突变小鼠易于发生侵袭性癌症。重要的是，当Junb和Pten通过局部Cre重组酶递送在成人前前列腺的小细胞群体中失活时，也会发生侵袭性肿瘤。由此产生的肿瘤显示出与人类前列腺癌很强的组织学相似性。JunB表达的缺失导致增殖增加和衰老减少，这可能是由于上皮细胞中p16（Ink 4a）和p（21 CIP 1）减少。此外，肿瘤间质改变，骨桥蛋白和S100钙结合蛋白A8/9表达增加，这与患者的不良预后相关。这些数据表明，JUNB/AP-1与PTEN信号传导合作作为侵袭性前列腺癌的屏障，其伴随的遗传或表观遗传抑制诱导恶性进展。
Prostate cancer is a frequent cause of male death in the Western world. Relatively few genetic alterations have been identified, likely owing to disease heterogeneity. Here, we show that the transcription factor JUNB/AP-1 limits prostate cancer progression. JUNB expression is increased in low-grade prostate cancer compared with normal human prostate, but downregulated in high-grade samples and further decreased in all metastatic samples. To model the hypothesis that this downregulation is functionally significant, we genetically inactivated Junb in the prostate epithelium of mice. When combined with Pten (phosphatase and tensin homologue) loss, double-mutant mice were prone to invasive cancer development. Importantly, invasive tumours also developed when Junb and Pten were inactivated in a small cell population of the adult anterior prostate by topical Cre recombinase delivery. The resulting tumours displayed strong histological similarity with human prostate cancer. Loss of JunB expression led to increased proliferation and decreased senescence, likely owing to decreased p16(Ink4a) and p(21CIP1) in epithelial cells. Furthermore, the tumour stroma was altered with increased osteopontin and S100 calcium-binding protein A8/9 expression, which correlated with poor prognoses in patients. These data demonstrate that JUNB/AP-1 cooperates with PTEN signalling as barriers to invasive prostate cancer, whose concomitant genetic or epigenetic suppression induce malignant progression.