Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China; Institute of Urology, Shanghai Jiao Tong University, Shanghai, 200080, China.
Department of Urology, Jiangsu Jiangyin People's Hospital, Jiangyin, 214400, China.
Cancer Lett. 2021 Apr 10;503:138-150. doi: 10.1016/j.canlet.2021.01.017. Epub 2021 Jan 24.
The androgen receptor (AR) is expressed in prostate fibroblasts in addition to normal prostate epithelial cells and prostate cancer (PCa) cells. Moreover, AR activation in fibroblasts dramatically influences prostate cancer (PCa) cell behavior. Androgen deprivation leads to deregulation of AR downstream target genes in both fibroblasts and PCa cells. Here, we identified LIM domain only 2 (LMO2) as an AR target gene in prostate fibroblasts using ChIP-seq and revealed that LMO2 can be repressed directly by AR through binding to androgen response elements (AREs), which results in LMO2 overexpression after AR deactivation due to normal prostate fibroblasts to cancer-associated fibroblasts (CAFs) transformation or androgen deprivation therapy. Next, we investigated the mechanisms of LMO2 overexpression in fibroblasts and the role of this event in non-cell-autonomous promotion of PCa cells growth in the androgen-independent manner through paracrine release of IL-11 and FGF-9. Collectively, our data suggest that AR deactivation deregulates LMO2 expression in prostate fibroblasts, which induces castration resistance in PCa cells non-cell-autonomously through IL-11 and FGF-9.
雄激素受体（AR）不仅在正常前列腺上皮细胞和前列腺癌（PCa）细胞中表达，还在前列腺成纤维细胞中表达。此外，成纤维细胞中 AR 的激活会显著影响前列腺癌（PCa）细胞的行为。雄激素剥夺会导致成纤维细胞和 PCa 细胞中 AR 下游靶基因的失调。在这里，我们使用 ChIP-seq 鉴定了 LIM 结构域只有 2 种（LMO2）作为前列腺成纤维细胞中的 AR 靶基因，并揭示了 LMO2 可以通过与雄激素反应元件（AREs）结合直接被 AR 抑制，导致 AR 失活后 LMO2 过表达，原因是正常前列腺成纤维细胞向癌相关成纤维细胞（CAFs）转化或雄激素剥夺治疗。接下来，我们研究了成纤维细胞中 LMO2 过表达的机制以及这种事件通过旁分泌释放 IL-11 和 FGF-9 以非细胞自主方式促进 PCa 细胞生长的作用。总的来说，我们的数据表明，AR 失活会使前列腺成纤维细胞中的 LMO2 表达失调，从而通过 IL-11 和 FGF-9 以非细胞自主的方式诱导 PCa 细胞的去势抵抗。
