E3泛素连接酶FBXO22在乳腺癌发生发展中的功能及其机制研究

Breast cancer is the most commonly diagnosed type of cancer and is a leading cause of cancer-related mortality in women worldwide. Thus, elucidation of the underlying mechanisms for breast cancer development and progression is one of the key scientific issues that need to be addressed urgently in the field of breast cancer research. Previous studies have demonstrated that F-box only protein 22 (FBXO22) exerts an E3 ubiquitin ligase activity. However, the biological functions and related molecular mechanisms for FBXO22 in the process of breast cancer development and progression remain unknown to date. Interestingly, we found that FBXO22 protein promotes breast cancer cell growth but suppresses breast cancer cell migrative and invasive potential in vitro. Clinical data from immunohistochemical analysis of FBXO22 protein expression in 164 primary breast cancer tissue specimens revealed that elevated FBXO22 expression positively correlates with better overall survival (OS) and disease-free survival (DFS), indicating that FBXO22 is a potential tumor suppressor for breast cancer development and progression. However, the biological functions of FBXO22 in breast cancer development and progression in vivo and its underlying mechanisms remain to be investigated. Based on those exciting findings, in the present project we aim to address the functional roles and the underlying mechanisms for FBXO22 in breast cancer development and progression using a variety of experimental models and techniques. To this end, the key scientific questions to be answered in this project include what are the ubiquitination substrates of FBXO22, how FBXO22 regulates the ubiquitination and proteasome-dependent degradation of those substrates, and what are the biological functions of the FBXO22-its substrate protein signaling axis in the process of breast cancer development and progression. The expected findings from this study will reveal the biological functions as well as the molecular mechanisms of FBXO22 protein in breast cancer development and progression, and will provide a breakthrough or basis for discovering new strategies for targeting breast cancer progression. Taken together, in the light of the solid research background and preliminary data, we strongly believe that this study is definitely feasible, and innovative and has the potential clinical translation implications.

阐明乳腺癌发生发展的分子机制是目前乳腺癌研究领域急需解决的关键科学问题之一。以前的研究证实F-box蛋白FBXO22具有E3泛素连接酶活性，但其在乳腺癌发生发展中的功能及其分子机制尚未见报道。我们前期研究发现，FBXO22在体外促进乳腺癌细胞生长但是抑制其迁移和侵袭潜能，临床数据表明FBXO22是一个潜在乳腺癌抑癌蛋白，但FBXO22在体内对乳腺癌发生发展的影响及其具体的分子机制尚不清楚。本项目拟采用多种实验模型和技术，系统性地解析FBXO22在乳腺癌发生发展中的功能及其分子机制。拟解决的关键科学问题包括鉴定FBXO22泛素化修饰的作用底物、阐明调控其底物蛋白泛素化修饰和降解的分子机制、以及明确FBXO22-底物蛋白信号轴在乳腺癌发生发展中的关键作用。本课题的研究成果将为揭示FBXO22蛋白在乳腺癌发生发展中的功能及分子机制以及促进发现新的干预乳腺癌进展的药物靶点提供重要线索。

肿瘤转移是目前导致肿瘤病人死亡的最主要原因，其确切的分子机制尚不清楚。本研究阐明了FBXO22蛋白在乳腺癌进展过程中发挥了双向的功能。首先，相较于癌旁组织，FBXO22蛋白在乳腺癌肿瘤组织中高表达，体内和体外实验表明其促进肿瘤细胞的增殖、克隆形成及动物成瘤能力。同时本研究发现，FBXO22蛋白抑制肿瘤细胞体内和体外迁移、侵袭和转移的能力。其次，乳腺肿瘤组织的免疫组化结果显示，FBXO22高表达与乳腺癌病人良好的预后正相关。分子机制研究表明，FBXO22蛋白通过泛素-蛋白酶体途径降解SNAIL蛋白，进而抑制上皮-间质转化（EMT）过程，并且此过程依赖于GSK3β激酶的磷酸化调控。此外，侵袭性乳腺癌患者来源样本中发现的FBXO22 W52R突变，本研究通过弱化FBXO22与SKP1-CULLIN1形成复合体的能力，抑制了FBXO22-SKP1-CULLIN1复合体泛素连接酶的活性，稳定了底物SNAIL蛋白，促进了肿瘤细胞的转移。综上所述，本研究首次报道了FBXO22蛋白在乳腺癌发生发展过程的功能，阐明了FBXO22 W52R失活突变促进乳腺癌侵袭的分子机制，支持了肿瘤转移而非原位癌是肿瘤致死的主要原因。