转录因子TEAD4在鼻咽癌转移中的作用及分子机制研究

Distant metastasis is the main cause of treatment failures in nasopharyngeal carcinoma (NPC). Therefore, identification of key molecular marker in the metastatic process of NPC, and clarification of its functions and mechanisms as well as its prognostic value, is a crucial way to achieve individualized treatment of NPC and improve the survival rate. To date, aberrant expression of transcription factors has been found to play an important role in the development and progression of NPC. Our previous study found that: ① The mRNA expression of transcription factor TEAD4 was significantly upregulated in metastatic versus non-metastatic NPC tissues, and in NPC versus normal cell lines as well; ② Silencing TEAD4 using shRNA significantly suppressed migration and invasion of NPC cells; however, the mechanism remains unknown. ③ Patients with high expression of TEAD4 had significantly higher risk of distant metastasis and also poorer prognosis. In this study, we will study the functions and mechanisms of TEAD4 in NPC metastasis in vitro and in vivo. Furthermore, we will detect the TEAD4 expression status in 400 NPC patients and examine its prognostic value for distant metastasis and survival. Through this research, it could provide a new target for the molecular classification and individualized treatment of NPC.

远处转移已成为制约鼻咽癌疗效提高的瓶颈，探寻与鼻咽癌远处转移相关的分子指标，阐明其功能和机制并明确其对转移及预后的预测价值，进而筛选出高远转风险的患者，指导个体化治疗，是提高鼻咽癌患者疗效的关键。鼻咽癌的发生发展与转录因子的异常表达关系密切，我们的前期研究显示：① 转录因子TEAD4在发生远处转移的鼻咽癌组织中表达显著升高，且在鼻咽癌细胞株中表达较正常鼻咽上皮细胞株显著升高。② 瞬转TEAD4的shRNA降低其表达后可显著抑制鼻咽癌细胞的迁移和侵袭能力，但具体作用机制不详。③ TEAD4高表达的鼻咽癌患者远处转移风险显著升高，预后显著变差。本项目拟在此基础上，通过体内外模型阐明转录因子TEAD4在促进鼻咽癌转移中的具体作用及分子机制；同时通过检测400例鼻咽癌组织中TEAD4的表达，进一步明确TEAD4表达水平对鼻咽癌患者远处转移及预后的预测价值，为鼻咽癌分子分型和个体化治疗提供新的靶点。

远处转移是目前鼻咽癌治疗失败的主要模式，在放疗基础上联合化疗或免疫治疗等全身疗法是其主要治疗策略。在精准医疗时代下，减少鼻咽癌转移的关键是鉴别出不同个体之间内在的转移潜能差异，筛选出高转移风险患者进行个体化治疗，并阐明相关分子机制，从而为转移的干预提供新靶点。在本课题的资助下，我们课题组取得了如下成果：①明确了癌基因TEAD4与鼻咽癌患者高转移风险密切相关，并阐明了TEAD4通过转录促进BZW2的表达进而激活AKT信号通路促进鼻咽癌转移的分子机制。为鼻咽癌的个体化抗转移治疗提供了分子预测指标和潜在治疗靶点。②在单细胞水平深入解析了鼻咽癌免疫微环境异质性，揭示了免疫微环境对肿瘤转移的重要调控作用，并基于微环境异质性建立了可指导精准免疫治疗的分子分型，从而提供了免疫抑制微环境的潜在干预靶点，锁定了免疫治疗获益目标人群。申请人以第一/通讯作者身份发表 SCI 论文 5 篇，包括 Cell Res (IF 25.6)、Ann Oncol (IF 33.0)、Mol Cancer (IF 27.4)、J Hematol Oncol (IF 17.4)、和J ImmunoTher Cancer (IF 13.8)等。并入选“中国科协青年人才托举工程（2021）”和“广东省自然科学基金杰出青年项目（2021）”，获得2021年度吴孟超医学青年基金奖和2020年度人民网“人民好医生”等奖励。