Centro de Biología Molecular "Severo Ochoa" (Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid), c/ Nicolás Cabrera, 1, Campus Cantoblanco, Universidad Autónoma de Madrid, Madrid 28049, Spain.
Departamento de Bioquímica, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), IdiPaz, Madrid, Spain; MD Anderson Cancer Center Madrid & Fundación MD Anderson Internacional, Madrid, Spain.
Neoplasia. 2019 Nov;21(11):1073-1084. doi: 10.1016/j.neo.2019.10.001. Epub 2019 Nov 14.
The role of prostaglandin (PG) F has been scarcely studied in cancer. We have identified a new function for PGF in ovarian cancer, stimulating the production of Prostate Transmembrane Protein, Androgen Induced 1 (PMEPA1). We show that this induction increases cell plasticity and proliferation, enhancing tumor growth through PMEPA1. Thus, PMEPA1 overexpression in ovarian carcinoma cells, significantly increased cell proliferation rates, whereas PMEPA1 silencing decreased proliferation. In addition, PMEPA1 overexpression buffered TGFβ signaling, via reduction of SMAD-dependent signaling. PMEPA1 overexpressing cells acquired an epithelial morphology, associated with higher E-cadherin expression levels while β-catenin nuclear translocation was inhibited. Notwithstanding, high PMEPA1 levels also correlated with epithelial to mesenchymal transition markers, such as vimentin and ZEB1, allowing the cells to take advantage of both epithelial and mesenchymal characteristics, gaining in cell plasticity and adaptability. Interestingly, in mouse xenografts, PMEPA1 overexpressing ovarian cells had a clear survival and proliferative advantage, resulting in higher metastatic capacity, while PMEPA1 silencing had the opposite effect. Furthermore, high PMEPA1 expression in a cohort of advanced ovarian cancer patients was observed, correlating with E-cadherin expression. Most importantly, high PMEPA1 mRNA levels were associated with lower patient survival.
前列腺素 (PG) F 在癌症中的作用研究甚少。我们已经确定了 PGF 在卵巢癌中的一个新功能，它可以刺激前列腺跨膜蛋白、雄激素诱导 1 (PMEPA1) 的产生。我们表明，这种诱导增加了细胞的可塑性和增殖能力，通过 PMEPA1 促进肿瘤生长。因此，卵巢癌细胞中 PMEPA1 的过表达显著增加了细胞的增殖率，而 PMEPA1 的沉默则降低了增殖率。此外，PMEPA1 的过表达通过减少 SMAD 依赖性信号转导缓冲了 TGFβ信号。过表达 PMEPA1 的细胞获得了上皮形态，同时 E-钙黏蛋白表达水平升高，而 β-连环蛋白的核转位受到抑制。尽管如此，高水平的 PMEPA1 也与上皮间质转化标志物（如波形蛋白和 ZEB1）相关，使细胞能够同时利用上皮和间质特征，从而获得更高的细胞可塑性和适应性。有趣的是，在小鼠异种移植模型中，过表达 PMEPA1 的卵巢细胞具有明显的存活和增殖优势，导致更高的转移能力，而 PMEPA1 的沉默则产生相反的效果。此外，在一组晚期卵巢癌患者中观察到高 PMEPA1 表达与 E-钙黏蛋白表达相关。最重要的是，高 PMEPA1 mRNA 水平与患者生存率降低相关。
