PURPOSE Metastatic prostate cancer (PCa) patients are increasingly presenting with treatment-resistant, androgen receptor-Negative/Low (AR-/Low) tumors, with or without neuroendocrine characteristics, in processes attributed to tumor cell plasticity. This plasticity has been modeled by Rb1/p53 knockdown/knockout and is accompanied by overexpression of the pluripotency factor, Sox2. Here we explore the role of the developmental transcription factor Sox9 in the process of PCa therapy response and tumor progression. EXPERIMENTAL DESIGN Unique PCa cell models that capture AR-/Low stem cell-like intermediates were analyzed for features of plasticity and the functional role of Sox9. Human PCa xenografts and tissue microarrays were evaluated for temporal alterations in Sox9 expression. The role of NF-κB pathway activity in Sox9 overexpression was explored. RESULTS PCa stem cell-like intermediates have reduced Rb1 and p53 protein expression and overexpress Sox2 as well as Sox9. Sox9 was required for spheroid growth, and overexpression increased invasiveness and neural features of PCa cells. Sox9 was transiently upregulated in castration-induced progression of PCa xenografts and was specifically overexpressed in neoadjuvant hormone therapy (NHT) treated patient tumors. High Sox9 expression in NHT-treated patients predicts biochemical recurrence. Finally, we link Sox9 induction to NF-κB dimer activation in PCa cells. CONCLUSIONS Developmentally reprogrammed PCa cell models recapitulate features of clinically-advanced prostate tumors including downregulated Rb1/p53 and overexpression of Sox2 with Sox9. Sox9 is a marker of a transitional state that identifies PCa cells under the stress of therapeutic assault and facilitates progression to therapy resistance. Its expression may index the relative activity of the NF-κB pathway.

中文翻译：

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瞬时Sox9表达有助于进展为去势抵抗性前列腺癌。

目的转移性前列腺癌（PCa）患者在归因于肿瘤细胞可塑性的过程中，越来越多出现具有治疗抵抗力，雄激素受体阴性/低（AR- /低）的肿瘤，无论是否具有神经内分泌特征。这种可塑性已通过Rb1 / p53敲除/敲除建模，并伴随着多能性因子Sox2的过表达。在这里，我们探索PCa治疗反应和肿瘤进展过程中发育转录因子Sox9的作用。实验设计分析了捕获AR- /低干细胞样中间体的独特PCa细胞模型的可塑性特征和Sox9的功能作用。评估人PCa异种移植物和组织微阵列的Sox9表达的时间变化。探索了NF-κB通路活性在Sox9过表达中的作用。结果PCa干细胞样中间体减少了Rb1和p53蛋白的表达，并过表达Sox2和Sox9。Sox9是球状体生长所必需的，过表达会增加PCa细胞的侵袭性和神经特征。Sox9在去势诱导的PCa异种移植进程中短暂上调，在新辅助激素治疗（NHT）治疗的患者肿瘤中特别过表达。NHT治疗的患者中高Sox9表达预示着生化复发。最后，我们将Sox9诱导与PCa细胞中的NF-κB二聚体激活联系起来。结论经过重新编程的PCa细胞模型可概括临床上先进的前列腺肿瘤的特征，包括Rb1 / p53的下调和Sox2与Sox9的过度表达。Sox9是一种过渡状态的标志物，可在治疗性攻击的压力下识别PCa细胞，并促进其发展为治疗耐药性。其表达可指示NF-κB途径的相对活性。