UBE2T为泛素偶联酶，我们分析发现UBE2T在乳腺癌等肿瘤中过表达且伴随较差预后。初步结果表明UBE2T能促进乳腺癌细胞增殖、迁移和侵袭及乳腺癌发生和转移；虽然UBE2T被认为是泛素偶联酶，但我们前期结果提示UBE2T可能通过竞争性阻断FBXW7对Vimentin的泛素化降解而发挥促癌作用。本课题拟在前期研究基础上①进一步明确UBE2T在乳腺癌发生、转移中的作用及机制；②分析UBE2T与FBXW7、Vimentin相互作用位点，在分子水平剖析其促癌机制；③应用乳腺组织特异性Ubet2转基因小鼠确认其作用及机制。期望通过上述研究明确UBE2T在乳腺癌发生、转移中的作用、分子机制及临床意义，为下一步探讨其可能的临床应用价值提供依据。申请人和合作者对泛素系统与肿瘤的关系有深厚研究经验，并有多年合作基础，本课题既是对UBE2T作用和机制的深入探讨，也是我们对FBXW7等泛素系统研究的延续和深入。

Bioinformatics analysis of gene expression array datasets revealed that UBE2T, an ubiquitin-conjugating enzyme, which was silent or rarely expression in normal tissues, was highly expressed in malignant cancers such as breast cancer and its expression level was correlated with metastasis and prognosis of cancer patients. However, little is known about its oncogenic roles. Our preliminary data confirmed that UBE2T could induce the malignant transformation, EMT of mammary cells and proliferation, migration, invasion, tumorigenesis and metastasis of breast cancer cells. Mechanistic analysis through TAP-MS, CoIP, protein degradation experiments implied that UBE2T and FBXW7 competitively bind to vimentin. FBXW7 binds vimentin to promote its proteasomal degradation, meanwhile, UBE2T binds vimentin to avoid proteasomal degradation and stabilize its protein level. However, more confirmative data are needed to validate its mechanistic role and clinical significance in breast cancer development and progression. Thus, this project is designed to: 1. further validate the oncogenic roles and related mechanisms of UBE2T in the development, metastasis of breast cancer and the formation of breast cancer stem cells; 2. Uncover its oncogenic mechanism at molecular level through identifying the interaction sites; 3. confirm its in vivo oncogenic role by application of our newly developed mammary-specific Ube2t transgenic mouse model. The applicant and collaborator in China have intensive experience in ubiquitin system and long-term, productive collaboration. This project is not only the intensive investigation of UBE2T, but also the continuation our previous research on ubiquitin system such as FBXW7.

UBE2T为泛素偶联酶，我们分析发现UBE2T在乳腺癌等肿瘤中过表达且伴随较差预后。初步结果表明UBE2T能促进乳腺癌细胞增殖、迁移和侵袭及乳腺癌发生和转移；虽然UBE2T被认为是泛素偶联酶，但我们前期结果提示UBE2T可能通过调控Vimentin的发挥促癌作用。经过研究我们发现①UBE2T能够促进乳腺癌发生、转移以及乳腺癌干细胞的特性；②分析UBE2T通过Vimentin发挥其促癌机制；③动物模型实验进一步证实UBE2T促进乳腺癌瘤体生长已发生远处转移的作用。我们通过上述研究明确UBE2T在乳腺癌发生、转移中的作用、分子机制及临床意义，为下一步探讨其可能的临床应用价值提供依据。