新信号轴miR-27a*-FBXO45-SIP1调控前列腺癌发生发展的分子机制

Prostate cancer is the most common malignancy in men, and its incidence has constantly increased in the past few decades. Like other cancer cells, prostate cancer cells are able to transfer from primary tissue to other parts of the body, especially to the bones and lungs. An increasing number of studies have uncovered that abberant expression of specific microRNAs and protein modification play important roles in type of cancers including prostate cancer， and closely related to the tumor occurrence and development.Preliminary results from our research group showed that: 1) miR-27a* can obviously regulate prostate cancer cell migration, invasion, and tumor genesis; 2) miR-27a* can raise the SIP1 protein expression level in prostate cancer cell; 3) SIP1 protein degradation can be significantly inhibited under MG132 treatment in vitro, which may also correlated with the expression of miR-27a*; 4) FBXO45 may be a potential target gene of miR-27a* and be responsible for degradation of the protein SIP1. In hence, we intends to focus on the regulation role of this special signal axis miR-27a*-FBXO45-SIP1 in tumor genesis, cell growth and metastasis to illuminate a new molecular mechanism in the developing progress of prostate cancer. This project will supply a new clinical reference and technical support for the prevention and treatment of prostate cancer.

前列腺癌是男性中最常见的恶性肿瘤，其发病率在过去的几十年内不断增高。与其它癌细胞一样，前列腺癌细胞可以从前列腺组织转移至身体其它部位，尤其是骨骼和肺脏。越来越多的研究证实，包括前列腺癌在内的各类肿瘤的发生发展与microRNA异常表达以及蛋白的修饰调控作用密切相关。与本项目相关的前期结果显示：1）miR-27a*能够明显调控前列腺癌细胞的转移、侵袭以及肿瘤形成；2） miR-27a*能够显著上调前列腺癌细胞中SIP1蛋白的表达水平； 3）MG132处理细胞能够抑制SIP1蛋白的降解，并且与miR-27a*的表达呈现相关性； 4)FBXO45可能是miR-27a*的一个潜在靶基因,并负责调控SIP1的泛素化降解。因此本项目拟从新信号轴miR-27a*-FBXO45-SIP1调控的肿瘤形成、细胞增殖以及转移来研究前列腺癌发生发展的新机制，本研究将为前列腺癌的防治提供新的临床参考依据和技术支撑。

表皮细胞向间质细胞转化（EMT）在促进肿瘤细胞迁移、侵袭和转移过程中起着重要的调节作用，通常伴随着E-钙粘蛋白的丧失和N-钙粘蛋白的增多，该过程主要受调于Zeb1、Zeb2（SIP1）、Snail1、Snail2（Slug）以及Twist1等EMT相关转录因子的调控。在本项目中，我们研究发现这些EMT相关转录因子能够被一个非典型的泛素E3连接酶组分蛋白Fbxo45介导发生蛋白酶体的降解。在生化机制上，Fbxo45能够通过不同的蛋白结构域识别不同的转录因子，比如其SPRY结构域识别Zeb1和Zeb2，而F-box结构域负责识别Snail1/2和Twist1，其中Zeb2（SIP1）发生泛素化修饰的主要依赖于其SBD结构域。与此同时，我们还发现Fbxo45受调控与miR-27a*，在前列腺癌细胞中过量表达的miR-27a*抑制了Fbxo45蛋白的翻译转录，从而阻碍了Fbxo45介导EMT相关转录因子的蛋白酶体降解过程，进而促进肿瘤细胞的EMT进程。本项目研究提出了miR-27a*-Fbxo45-EMT-TF信号轴中，fbxo45是一个关键点调控节点。本研究为临床上诊断肿瘤转移、恶性转化提供更广泛的数据参考，也为肿瘤的治疗研究提供了新的策略和思路。