Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Men's Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia.
ACRF Cancer Genomics Facility, Centre for Cancer Biology, An alliance of SA Pathology and University of South Australia, Frome Road, Adelaide, SA 5005, Australia.
Cell Rep. 2021 Jan 5;34(1):108585. doi: 10.1016/j.celrep.2020.108585.
Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signaling. miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.
雄激素受体（AR）的有效治疗抑制可导致前列腺腺癌中神经内分泌前列腺癌（NEPC）的出现，这与增强的细胞可塑性有关。在这里，我们表明 microRNA-194（miR-194）是上皮-神经内分泌转化的调节剂。在临床前列腺癌样本中，NEPC 中 miR-194 的表达和活性升高，与 AR 信号呈负相关。miR-194 促进了前列腺癌细胞中神经内分泌特征的出现，这一过程是通过其直接靶向参与细胞可塑性的一系列基因的能力介导的。FOXA1 是其中一个靶标，其编码转录因子，在维持前列腺上皮谱系中起着至关重要的作用。重要的是，miR-194 抑制剂阻断了上皮-神经内分泌转化，并抑制了具有神经内分泌特征的细胞系和患者衍生类器官的生长。总的来说，我们的研究揭示了一种调节前列腺癌细胞可塑性的转录后机制，并为靶向 NEPC 中的 miR-194 提供了依据。
