原癌基因RET在前列腺癌恶性转移中的作用和机制研究

Bone metastasis remains the major cause of death in advanced prostate cancer (PCa). However, the underlying mechanisms involve in the homing of prostate tumor cells to the bone are largly unknown. Bone cells produce and secrete glial cell line-derived neurotrophic factor (GDNF), which has strong chemotactic ability. The RET proto-oncogene, a signaling component in a multisubunit receptor complex for GDNF, is highly expressed in aggressive prostate cancer, but the the relation between RET and bone metastasis in prostate cancer is unclear. We previously found that overexpression of RET would significantly promote prostate cancer cell metastasis to bone cell, while blocking RET internalization could suppress this process. We supposed that RET is great importance for bone metastasis in PCa because RET provides structure condition for chemotaxis of GNDF produced by bone cells. To assess the significance of RET in PCa metastasis, some tests were designed as follows: firstly, to investigate the association between RET expression and prostate cancer progression by using the prostate cancer tissue chip; secondly, to figure out the effects of RET on biological properties of LNCaP cells in vitro and in vivo via gain or loss of function of RET, as well as to evaluate whether the role of RET in LNCaP cells is correlative to androgen receptor signaling; thirdly, to determine the influence of RET internalization on prostate cancer metastasis. By systemic analysis the function and mechanism of RET on PCa metastasis, we expect to provide a potential target for the treatment of bone metastases in advanced-stage prostate cancer.

骨转移是导致前列腺癌患者死亡的主要原因，而前列腺癌细胞为何显著倾向于向骨转移，其机制尚不清楚。骨细胞可以表达和分泌胶质细胞源性神经营养因子(GDNF),后者具备很强的趋化能力。RET既是原癌基因，又是GDNF家族的共受体，在晚期前列腺癌中表达升高，具体作用不明。项目组前期工作发现：过表达RET促进前列腺癌细胞向骨细胞迁移，阻止RET内化明显抑制此过程。我们设想RET的表达为骨细胞中GDNF的趋化作用提供了结构基础，是促使前列腺癌恶性转移的重要因素。为了衡量RET对前列腺癌进展的重要性，本课题拟做到：1.利用组织芯片分析RET的表达与临床生存期及转移的关系；2. 利用功能获得与缺失实验，在细胞水平和动物水平分析RET对前列腺癌细胞生物学特性的影响，并检测其和雄激素受体的关系；3.进一步探讨RET内化对前列腺癌细胞迁移的影响。希望通过这些工作为晚期前列腺癌骨转移的治疗提供实验依据和新的靶点。

骨转移是导致前列腺癌患者死亡的主要原因，而前列腺癌细胞为何显著倾向于向骨转移，其机制尚不清楚。骨细胞可以表达和分泌胶质细胞源性神经营养因子(GDNF),后者具备很强的趋化能力。RET既是原癌基因，又是GDNF家族的共受体，在晚期前列腺癌中表达升高，具体作用不明。项目组前期工作发现：过表达RET促进前列腺癌细胞向骨细胞迁移，阻止RET内化明显抑制此过程。我们设想RET的表达为骨细胞中GDNF的趋化作用提供了结构基础，是促使前列腺癌恶性转移的重要因素。为了衡量RET活化后对前列腺癌进展的重要性，本课题利用功能获得与缺失实验，在细胞水平和动物水平以及临床病理和随访统计分析，探讨一系列RET活化蛋白对前列腺癌细胞迁移的影响。希望通过这些工作为晚期前列腺癌骨转移的治疗提供实验依据和新的靶点。