SIRT6通过调控NOTCH信号及外泌体功能促进前列腺癌转移的机制研究

肿瘤转移是日益高发的前列腺癌难治的最主要原因之一，其复杂的调控机制，包括肿瘤细胞上皮间质转化（EMT）和肿瘤微环境的作用，仍有诸多问题尚待阐明。在前期研究中我们报道了关键调控蛋白SIRT6的促癌作用，其高表达与前列腺癌细胞的转移以及病人的不良预后正相关。预实验初步提示SIRT6调控前列腺癌细胞EMT、Notch信号以及外泌体分泌的作用。为进一步明确SIRT6促进前列腺癌细胞转移的分子机制，我们拟围绕“SIRT6通过调控Notch信号促进前列腺癌细胞EMT和转移”和“SIRT6调控前列腺癌细胞分泌外泌体并作用于肿瘤微环境的细胞如肿瘤相关成纤维细胞，进而促进前列腺癌细胞转移”的研究假说，从细胞模型、动物模型、临床样本和数据分析入手，多角度开展实验研究，为临床开发阻断前列腺癌转移的治疗方法提供新的思路和依据。

Metastasis is the key factor that contributes to the prostate cancer-associated death, which type of cancer is occurring more and more frequently worldwide. Epithelial-mesenchymal transition (EMT) is the critical biological mechanism that underlies tumor metastasis, whereas the tumor microenvironment is also a key player in this process. Many questions with regard to the mechanisms of prostate cancer metastasis remain to be answered. In our previous study, we reported that SIRT6, a key regulatory gene, could promote prostate cancer and its high expression correlated to the metastasis and poor prognosis. Preliminary experiments also indicated that SIRT6 regulated EMT and Notch signals, which might also affect exosome secretion. In this project, we will carry out the following studies to confirm: (1) the function of SIRT6 in promoting EMT in prostate cancer cells and their metastasis in vivo; (2) that Notch signaling actually mediates the function of SIRT6 as in (1); and importantly, (3) SIRT6 regulates prostate cancer cell in exosome secretion and function that acts upon cancer-associated fibroblasts in the tumor microenvironment, which in turn, promote the metastases of prostate cancer cells. This research will provide new insights and suggest new therapeutic targets for prostate cancer metastasis.