PPARγ激动剂罗格列酮通过DKK1诱导的Wnt信号通路抑制前列腺癌骨转移的作用机制研究

Prostate cancer is the most common diagnosed cancer in males, and it displays an uncanny ability to metastasize to the bone. Delay or inhibit bone metastasis tends to be one of the most important therapeutic regimens. Our clinical investigation found that overexpression of DKK-1 by osteoblasts in Paget’s disease of bone (PDB) patients can elevated the serum level of DKK1, which was associated with improved survival of prostate cancer associated with PDB patients and elongated the time between diagnosis and bone metastasis. Furthermore, rosiglitazone (PPARγ inhibitor) showed a dose-dependent inhibition of the proliferation of TRAMP-C1 mouse prostate cancer cells, and arrested prostate cancer cells at S phase. Therefore, it is highly possible that rosiglitazone and DKK-1 play important role in anti-bone metastasis of prostate cancer. Based on previous studies, we plan to study the anti-metastasis role of DKK-1/Wnt pathway using prostate cancer clinical samples, and further investigate the mechanisms of rosiglitazone in regulation DKK-1/Wnt or related pathways using PDB mouse models and SCID human prostate cancer bone metastasis mouse model. The results will provide novel insights into the mechanisms and targets of rosiglitazone in inhibiting metastasis of prostate cancer. This study can help to explore new PPARγ activators for the prevention of bone metastasis in early stage prostate cancer patients.

前列腺癌是男性发病率最高同时也是最易发生骨转移的肿瘤之一，因此抑制或延缓前列腺癌骨转移非常重要。本课题组临床研究发现Paget骨病（Paget’s disease of bone）患者血清中高水平的Dickkopf-1（DKK1）与前列腺癌患者骨转移延缓及总生存期提高相关，而且PPARγ激动剂罗格列酮能诱导DKK1的表达，抑制前列腺癌细胞增殖和迁移，延长前列腺癌患者生存期。因此罗格列酮和DKK1作为潜在关键调节因素可能在抑制前列腺癌骨转移中起重要作用，但具体机制尚缺乏研究。本课题拟在此基础上，利用单纯前列腺癌及PDB合并前列腺癌临床样本探讨DKK1/Wnt通路在改善前列腺癌骨转移中的作用，并进一步利用PDB及前列腺癌小鼠模型探讨罗格列酮调节DKK1及下游相关通路的分子机制，验证罗格列酮改善前列腺癌预后的效果和作用靶点，为开发新型PPARγ激动剂用于防治前列腺癌奠定理论和临床前基础。

前列腺癌是男性发病率最高同时也是最易发生骨转移的肿瘤之一，因此抑制或延缓前列腺癌骨转移非常重要。我们通过对有PDB的前列腺癌患者及无PDB的前列腺癌病人回顾性病例研究发现，PDB合并前列腺癌患者进展为骨转移的过程较慢，在前列腺癌骨转移组织中DDK1的表达明显低于未发生骨转移组。PDB能够明显改善前列腺癌患者总生存期，并延缓骨转移时间，PDB可以作为总生存率和肿瘤诊断与骨转移检测时间的一个显著预测指标。而且PPARγ激动剂罗格列酮能诱导DKK1的表达，抑制前列腺癌细胞增殖和迁移，延长前列腺癌患者生存期。比格列酮通过影响DKK1/Wnt信号通路来调节破骨和成骨形成以及前列腺癌细胞存活，对前列腺癌骨转移有类似PDB的负向调节效应。后期我们将深入研究对于TZDs及DKK1/Wnt通路在抑制前列腺癌转移中的具体作用机制，探讨PPARγ激动剂罗格列酮抑制前列腺癌骨转移的分子机理及二级预防效果，为开发新型PPARγ激动剂用于防治前列腺癌奠定理论和临床前基础。