Department of Urology, RenJi Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China.
School of Biomedical Engineering, Shanghai Jiaotong University, Shanghai, People's Republic of China.
J Cell Biochem. 2018 Sep;119(9):7319-7327. doi: 10.1002/jcb.27030. Epub 2018 May 15.
Castration-resistant prostate cancers (CRPC) that occur after the failure of androgen-blocking therapies cause most of the deaths in prostate cancer (PCa) patients. In a previous study we identified that PRKAR2B expression is upregulated in CRPC and possesses potentials to develop CRPC. Here we further investigated the underlying mechanism of PRKAR2B in regulating prostate cancer metastasis. We established an androgen-independent LNCaPcell line (LNCaP-AI), and investigated the function of PRKAR2B on regulating cell invasion in vitro and in vivo. We found that PRKAR2B expression was markedly increased in LNCaP-AI cells and metastatic CRPC (mCRPC) tissues compared to LNCaP cells and primary PCa specimens, respectively. PRKAR2B level was significantly correlated with the Gleason score and lymph nodes metastasis in PCa. In vitro, PRKAR2B overexpression promoted cell invasion, whereas knockdown of PRKAR2B in CRPC cells inhibited cell invasion. PRKAR2B overexpression also promoted tumor metastasis in vivo. PRKAR2B resulted in a decreased expression of E-cadherin and an increased expression of Vimentin, N-cadherin, Fibronectin, indicating that PRKAR2B induced epithelial-mesenchymal transition (EMT). PRKAR2B activated Wnt/β-catenin signaling in CRPC cells. More important, inhibition of Wnt/β-catenin attenuated PRKAR2B-induced EMT and cancer cells invasion. Our results provided novel insights to PRKAR2B-driven CRPC cell invasion and indicated that PRKAR2B might be served as a potential target for CRPC therapy.
去势抵抗性前列腺癌（CRPC）在雄激素阻断治疗失败后发生，导致大多数前列腺癌（PCa）患者死亡。在之前的研究中，我们发现 PRKAR2B 在 CRPC 中表达上调，并具有发展为 CRPC 的潜力。在这里，我们进一步研究了 PRKAR2B 在调节前列腺癌转移中的潜在机制。我们建立了一种雄激素非依赖性 LNCaP 细胞系（LNCaP-AI），并研究了 PRKAR2B 在体外和体内调节细胞侵袭的功能。我们发现，与 LNCaP 细胞和原发性 PCa 标本相比，PRKAR2B 在 LNCaP-AI 细胞和转移性 CRPC（mCRPC）组织中的表达明显增加。PRKAR2B 水平与 PCa 的 Gleason 评分和淋巴结转移显著相关。在体外，PRKAR2B 过表达促进细胞侵袭，而在 CRPC 细胞中敲低 PRKAR2B 则抑制细胞侵袭。PRKAR2B 过表达也促进了体内肿瘤转移。PRKAR2B 导致 E-钙黏蛋白表达减少，波形蛋白、N-钙黏蛋白、纤连蛋白表达增加，表明 PRKAR2B 诱导上皮-间充质转化（EMT）。PRKAR2B 激活了 CRPC 细胞中的 Wnt/β-catenin 信号通路。更重要的是，抑制 Wnt/β-catenin 减弱了 PRKAR2B 诱导的 EMT 和癌细胞侵袭。我们的研究结果为 PRKAR2B 驱动的 CRPC 细胞侵袭提供了新的见解，并表明 PRKAR2B 可能成为 CRPC 治疗的潜在靶点。
