Androgen receptor variant-7 regulation by tenascin-c induced src activation.
Androgen receptor variant-7 regulation by tenascin-c induced src activation.
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DOI：
10.1186/s12964-022-00925-0
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发表时间：
2022-08-10
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骨转移性前列腺癌对雄激素靶向治疗没有完全反应，并且通常演变成致命的去势抵抗性前列腺癌（CRPC）。AR-V7- a的组成型活性、配体非依赖性AR剪接变体的表达是调节转移性CRPC的关键耐药机制之一。TNC是一种细胞外基质糖蛋白，对前列腺癌进展至关重要，并与前列腺癌骨转移有关。在这项研究中，我们研究了调节前列腺癌细胞与成骨微环境（包括TNC）相互作用中AR-V7表达的机制。使用RT-qPCR通过免疫荧光成像和基因表达分析评估前列腺癌/前成骨细胞异型类器官，以评估细胞区室化、TNC定位，并研究前成骨细胞和激素或抗雄激素作用对前列腺癌细胞中AR-V7的调节。使用RT-qPCR、蛋白质印迹、放线菌酮追踪测定和免疫荧光成像评估在TNC上培养的前列腺癌细胞，以评价（1）AR-V7的调节和（2）由TNC激活的信号传导途径。使用siRNA和小分子抑制剂靶向TNC诱导的已鉴定的信号通路，以研究TNC诱导的信号激活在AR-V7调节中的作用。使用siRNA靶向AR-V7和TNC诱导的信号传导效应物，并评估TNC表达以评估潜在的反馈调节。利用异型类器官，我们表明TNC是前列腺癌与前成骨细胞相互作用的组成部分。与前成骨细胞的相互作用上调了前列腺癌细胞中TNC和AR-V7的表达，这被睾酮抑制，但被抗雄激素Enzalutamide升高。有趣的是，结果表明，TNC诱导的Src激活调节前列腺癌细胞中的AR-V7表达、翻译后稳定性和核定位。用TNC中和抗体处理、Src敲低和Src激酶活性抑制AR-V7转录物和蛋白。反过来，观察到活化的Src和AR-V7都上调前列腺癌细胞中的自分泌TNC基因表达。总的来说，研究结果表明，前列腺癌细胞与成骨微环境中的细胞和ECM组分的相互作用在调节与转移性CRPC相关的AR-V7中起着关键作用。视频摘要在线版本包含补充材料，可通过10. 1186/s12964-022-00925-0获取。
Bone metastatic prostate cancer does not completely respond to androgen-targeted therapy and generally evolves into lethal castration resistant prostate cancer (CRPC). Expression of AR-V7- a constitutively active, ligand independent splice variant of AR is one of the critical resistant mechanisms regulating metastatic CRPC. TNC is an extracellular matrix glycoprotein, crucial for prostate cancer progression, and associated with prostate cancer bone metastases. In this study, we investigated the mechanisms that regulate AR-V7 expression in prostate cancer cells interacting with osteogenic microenvironment including TNC. Prostate cancer/preosteoblast heterotypical organoids were evaluated via immunofluorescence imaging and gene expression analysis using RT-qPCR to assess cellular compartmentalization, TNC localization, and to investigate regulation of AR-V7 in prostate cancer cells by preosteoblasts and hormone or antiandrogen action. Prostate cancer cells cultured on TNC were assessed using RT-qPCR, Western blotting, cycloheximide chase assay, and immunofluorescence imaging to evaluate (1) regulation of AR-V7, and (2) signaling pathways activated by TNC. Identified signaling pathway induced by TNC was targeted using siRNA and a small molecular inhibitor to investigate the role of TNC-induced signaling activation in regulation of AR-V7. Both AR-V7- and TNC-induced signaling effectors were targeted using siRNA, and TNC expression assessed to evaluate potential feedback regulation. Utilizing heterotypical organoids, we show that TNC is an integral component of prostate cancer interaction with preosteoblasts. Interaction with preosteoblasts upregulated both TNC and AR-V7 expression in prostate cancer cells which was suppressed by testosterone but elevated by antiandrogen enzalutamide. Interestingly, the results demonstrate that TNC-induced Src activation regulated AR-V7 expression, post-translational stability, and nuclear localization in prostate cancer cells. Treatment with TNC neutralizing antibody, Src knockdown, and inhibition of Src kinase activity repressed AR-V7 transcript and protein. Reciprocally, both activated Src and AR-V7 were observed to upregulate autocrine TNC gene expression in prostate cancer cells. Overall, the findings reveal that prostate cancer cell interactions with the cellular and ECM components in the osteogenic microenvironment plays critical role in regulating AR-V7 associated with metastatic CRPC. Video Abstract The online version contains supplementary material available at 10.1186/s12964-022-00925-0.
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