PICT-1对雄激素抵抗前列腺癌相关通路负反馈作用机制研究

Emergence of hormonal refractory prostate cancer(HRPC) remains the tough problem for urologists. The loss of phosphatase and tensin homologue deleted on chromosome 10(PTEN) is likely the first step towards the development of HRPC,while relevant mechanism and how it works still need to be investigated. Recent studies demonstated that protein interacting with carboxyl terminus(PICT-1) was closely related with PTEN and PI3K. However, there are no investigations in prostate cancer. Already, we have observed that the expression of PICT-1 and PTEN decreased while PI3K/Akt/mTOR pathway was activated in prostate cancer. Based on the findins and previous studies, we hypothsis that PICT-1, known as the regulator of PTEN which is the upstream of PI3K/Akt/mTOR pathway and could make great effect on it, could delay the development of HRPC via stabilizing PTEN, meanwhile depressing PI3K/Akt/mTOR pathway and AR pathway to restrain tumor growth and migration. Based on the assumption, following researches are designed. Firstly, we need to further demonstrate the interaction of PTEN and PICT-1in prostate cancer cell lines, regulation of PICT-1 results in the instability of PTEN, leading to the biological behavior disturbance of cells. Secondly, comparison of the reflect after inhibiting PI3K/Akt/mTOR and AR pathway or both when PICT-1 was up/down regulated. In addition, to find out the prognostic biomarkers of the therapies and investigate the expressions of these biomarkers in the prostate cancer samples. As a result, this program has the potential to provide the evidence for personalized target therapy when delaying the progression of HRPC.

前列腺癌治疗目前最大的难题是雄激素抵抗性前列腺癌（HRPC）的发生。PTEN的缺失突变可能是HRPC发生第一步，缺乏相关机制和如何调控的研究。近年来发现PICT-1与PTEN及PI3K通路关系密切，但在前列腺癌中无相关研究。我们前期工作发现前列腺癌中PICT-1和PTEN表达降低，PI3K通路激活相关，推论作为PI3K通路上游PTEN的调节基因PICT-1，也许可以通过稳定PTEN状态来延缓HRPC的发生，同时抑制PI3K/Akt/mTOR通路和AR通路。基于此假说，我们备调节PICT-1的表达来改变PTEN状态，探讨二者相互作用，对前列腺癌细胞的生物学行为的影响；比较前列腺癌细胞中PICT-1表达改变对PI3K和AR通路抑制剂以及联合用药的反应性；筛选出预测疗效的指标，并在体内实验验证药物疗效。为前列腺癌患者选择恰当的靶向药物延缓HRPC进展提供实验室依据。

前列腺癌治疗目前最大的难题是去势抵抗性前列腺癌（CRPC）的发生。PTEN的缺失突变可能是CRPC发生第一步，近年来发现PICT-1与PTEN及PI3K通路关系密切。我们前期工作发现前列腺癌中PICT-1和PTEN表达降低、PI3K通路激活相关。PICT-1作为PI3K通路上游的调节基因，可以通过稳定PTEN状态来延缓CRPC 的发生，同时抑制 PI3K/Akt/mTOR 通路。在前列腺癌中扮演抑癌基因的角色。PICT-1的阻断使前列腺癌细胞DU145对PI3K/Akt/mTOR抑制剂抵抗，该作用可以被恩杂鲁胺阻断。为今后联合应用PI3K/Akt/mTOR抑制剂与AR抑制剂恩杂鲁胺的临床试验提供了新的研究依据。