LMO2 upregulation due to AR deactivation in cancer-associated fibroblasts induces non-cell-autonomous growth of prostate cancer after androgen deprivation
LMO2 upregulation due to AR deactivation in cancer-associated fibroblasts induces non-cell-autonomous growth of prostate cancer after androgen deprivation
复制标题
雄激素剥夺后，癌症相关成纤维细胞中 AR 失活导致 LMO2 上调，诱导前列腺癌非细胞自主生长
DOI：
10.1016/j.canlet.2021.01.017
复制
发表时间：
2021-02-05
期刊：
影响因子：
9.7
通讯作者：
Zhao, Fu-Jun
中科院分区：
文献类型：
--
作者：
Chen, Lei;Wang, Yue-Yang;Zhao, Fu-Jun
除了正常前列腺上皮细胞和前列腺癌（PCa）细胞外，雄激素受体（AR）还在前列腺成纤维细胞中表达。此外，成纤维细胞中的 AR 激活显着影响前列腺癌 (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 鉴定了仅 LIM 结构域 2 (LMO2) 作为前列腺成纤维细胞中的 AR 靶基因，并揭示 LMO2 可以通过与雄激素反应元件 (ARE) 结合而直接被 AR 抑制，这导致由于正常前列腺成纤维细胞向癌症相关成纤维细胞 (CAF) 转化或雄激素剥夺治疗导致 AR 失活后 LMO2 过度表达。接下来，我们研究了成纤维细胞中 LMO2 过表达的机制，以及该事件通过旁分泌释放 IL-11 和 FGF-9 以不依赖雄激素的方式非细胞自主促进 PCa 细胞生长的作用。总的来说，我们的数据表明，AR 失活会解除前列腺成纤维细胞中 LMO2 表达的调节，从而通过 IL-11 和 FGF-9 非细胞自主地诱导 PCa 细胞的去势抵抗。
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.