文章：

Dickkopf-1（DKK1）在去势抵抗性前列腺癌中驱动肿瘤生长和转移

Dickkopf-1 (DKK1) drives growth and metastases in castration-resistant prostate cancer 

原文发布日期：2024-05-13 

英文摘要：

Metastatic castration-resistant prostate cancer (mCRPC) is associated with a poor prognosis and remains an incurable fatal disease. Therefore, the identification of molecular markers involved in cancer progression is urgently needed to develop more-effective therapies. The present study investigated the role of the Wnt signaling modulator Dickkopf-1 (DKK1) in the growth and metastatic progression of mCRPC. DKK1 silencing through siRNA and deletion via CRISPR/Cas9 editing were performed in two different metastatic castration-resistant prostate cancer cell lines (PC3 and DU145). A xenograft tumor model was used to assess tumor growth and metastases. In in vitro experiments, both DKK1 silencing and deletion reduced cell growth and migration of both cell lines. DKK1 knockout clones (DKK1-KO) exhibited cell cycle arrest, tubulin reorganization, and modulation of tumor metastasis-associated genes. Furthermore, in DKK1-KO cells, E-cadherin re-expression and its membrane co-localization with β-catenin were observed, contributing to reduced migration; Cadherin-11, known to increase during epithelial-mesenchymal transition, was down-regulated in DKK1-KO cells. In the xenograft mouse model, DKK1 deletion not only reduced tumor growth but also inhibited the formation of lung metastases. In conclusion, our findings support the key role of DKK1 in the growth and metastatic dissemination of mCRPC, both in vitro and in vivo. 

摘要翻译：

转移性去势抵抗性前列腺癌（mCRPC）预后较差，目前仍是一种无法治愈的致命疾病。因此，亟需鉴定参与癌症进展的分子标志物以开发更有效的治疗方法。本研究探讨了Wnt信号调节因子Dickkopf-1（DKK1）在mCRPC生长和转移进展中的作用。通过siRNA沉默和CRISPR/Cas9编辑敲除两种不同转移性去势抵抗性前列腺癌细胞系（PC3和DU145）中的DKK1，并采用异种移植肿瘤模型评估肿瘤生长和转移。体外实验表明，DKK1沉默与敲除均能抑制两种细胞系的生长和迁移。DKK1敲除克隆（DKK1-KO）表现出细胞周期阻滞、微管蛋白重组和肿瘤转移相关基因的调控。此外，在DKK1-KO细胞中观察到E-钙黏蛋白重新表达及其与β-连环蛋白的膜共定位，从而抑制细胞迁移；而上皮-间质转化过程中会增加的钙黏蛋白-11在DKK1-KO细胞中表达下调。在异种移植小鼠模型中，DKK1敲除不仅减缓了肿瘤生长，还抑制了肺转移灶的形成。总之，我们的研究结果证实了DKK1在mCRPC生长和转移扩散中的关键作用，这一结论在体外和体内实验中得到一致验证。

原文链接：

Dickkopf-1 (DKK1) drives growth and metastases in castration-resistant prostate cancer