TRIM71通过作用于HIF1α信号通路介导的上皮间质转化抑制宫颈癌转移的作用及机制研究

Cervical cancer is one of the most common malignant tumors in women, and its metastasis is the main reason of disease progression, relapse and tumor-related death. The role of TRIM71 in cervical cancer growth and metastasis remains unclear. Previously, we found TRIM71 was frequently down-regulated in cervical cancer cells and tissues, and its low-expression indicated poor prognosis. TRIM71 suppressed proliferation, invasion and migration, and epithelial-mesenchymal transition (EMT) of cervical cancer cells. The preliminary mechanism study demonstrated TRIM71 could inhibit the activation of HIF1α signaling pathway. TRIM71 is a kind of E3 ubiquitin ligase. Therefore we speculated that TRIM71 could inhibit HIF1α signaling-mediated EMT by degradation of HIF1α via ubiquitination, and thus suppress cervical cancer metastasis. To confirm this speculation, we will firstly validate TRIM71 suppress cervical cancer EMT and metastasis in vitro and in vivo. Then we will identify whether the deactivation of HIF1α signaling by TRIM 71 is through degradation of HIF1α via ubiquitination. Last but not least, we will also explore the molecular mechanism of TRIM71 down-regulation in cervical cancer. In the present study, we will systematically investigate the role of TRIM71 in cervical cancer EMT and metastasis, which will contribute to deeply clarify the regulatory network of cervical cancer progression and also provide theoretical foundation for individualized therapy.

宫颈癌是女性常见的恶性肿瘤，而发生转移是宫颈癌患者病情进展、复发及死亡的最主要原因。TRIM71在宫颈癌恶性进程中的作用尚未见报道。我们的前期研究发现：TRIM71在宫颈癌细胞和组织中表达下调，其低表达预示宫颈癌患者预后不良；TRIM71抑制宫颈癌细胞增殖、侵袭迁移和上皮间质转化（EMT）；初步机制研究显示TRIM71可抑制HIF1α信号通路活化。而TRIM71具有E3泛素连接酶活性。由此我们假设：TRIM71在宫颈癌中通过泛素化降解HIF1α抑制HIF1α信号通路介导的EMT，从而抑制宫颈癌转移。为此，我们拟体外、体内实验证实TRIM71可抑制宫颈癌EMT及转移，进而阐明其是否通过泛素化降解HIF1α抑制HIF1α信号通路，并探究TRIM71在宫颈癌中表达下调的分子机理。本项目将深入研究TRIM71在宫颈癌转移中的作用与机制，为完善宫颈癌的进程调控网络并进而基于此的精准治疗提供理论依据。

宫颈癌是女性常见的恶性肿瘤，而发生转移是宫颈癌患者病情进展、复发及死亡的最主要原因。TRIM71在宫颈癌恶性进程中的作用尚未见报道。我们的研究发现：TRIM71在宫颈癌细胞和组织中表达下调，其低表达预示宫颈癌患者预后不良；体外和体内功能实验显示TRIM71抑制宫颈癌细胞上皮间质转化（EMT）和增殖转移；机制探究发现TRIM71通过直接结合Nectin-4 mRNA 3’-UTR并抑制其翻译，继而抑制Wnt/β-catenin信号通路的活化，从而抑制宫颈癌细胞发生EMT和增殖转移。在此基础上，进一步揭示了TRIM71抑制宫颈癌血管新生的可能机制：TRIM71通过其C-端NHL结构域直接结合Nectin-4 mRNA的3’-UTR并抑制其翻译，使得从宫颈癌细胞膜脱落到肿瘤微环境中的Nectin-4胞外域减少，与邻近内皮细胞表面Integrin-β4结合减少，继而内皮细胞内的Src-PI3K-AKT-iNOS通路活化降低，进而抑制血管新生。本项目深入研究了TRIM71在宫颈癌转移中的作用与机制，为完善宫颈癌的进程调控网络并进而基于此的精准治疗提供理论依据。