多模态超声成像参数预测PTMC侵袭性的分子病理学基础研究

The incidence of thyroid papillary microcarcinoma(PTMC) is increasing rapidly. Accurate prediction of PTMC invasiveness may have a great impact on the current therapeutic strategy of "immediate surgery after diagnosis" which seems unnecessary and excessive since most PTMC cases are stable with low aggressiveness. While there still lacks methods for precise assessment of the progression ability of PTMC. In our previous study, we revealed that multimodality ultrasound evaluation had great potential for PTMC invasiveness prediction. However, the information acquired by this methodology reveals only physical profiles which lack connection to the innate molecular pathological status that determines the invasive ability as well as the macroscopical features of the lesions. Based on our findings and other scientists' reports, we propose that investigation of the molecular pathological basis for driving the variations of the multimodality ultrasonographic parameters of PTMC will improve the accuracy of precise assessment of PTMC invasiveness by ultrasonography. In this project, on establishment of our multimodality ultrasound database of thyroid lesions, we will, 1) set up the multimodality ultrasound database of for PTMC; 2) screen the molecular biomarkers for prediction of PTMC aggressiveness; 3) establish a predictive model for PTMC aggressiveness by combination of the multimodality ultrasound parameters and molecular biomarker status; 4) investigate the molecular pathological basis for the difference of PTMC multimodality ultrasound parameters by overexpressing/knocking out interested molecules in PTMC cells forming xenograft tumors in vivo. With the aim to satisfy the individual treatment demand of PTMC with different invasive abilities, our study has great siginificance for accurate prediction of the PTMC aggressiveness.

甲状腺微小乳头状癌（PTMC）发病率增长迅速，实现其侵袭性的精准评估可能会改变PTMC“发现即手术”的诊治现状，但目前尚缺乏妥善评估方法。我们发现，多模态超声成像对预测甲状腺癌侵袭性具有很高的价值，但其宏观层面评估病灶特征缺乏分子病理学的依据与支持。结合国内外进展，我们认为，探索侵袭性相关多模态超声参数的分子病理学驱动机制，将有助于实现超声无创化精准预判PTMC侵袭性。本项目拟在前期甲状腺疾患多模态超声成像研究的基础上，（1）建立PTMC多模态超声数据库；（2）在PTMC组织中筛选侵袭相关分子标志物；（3）建立多模态超声联合分子标志物评估PTMC侵袭性的模型；（4）在侵袭性相关兴趣分子过表达/敲除的PTMC动物模型水平探索相关超声模态特征的分子病理学基础。本项目从PTMC个体化临床处理的需求出发，对术前精准预判PTMC侵袭性有重要意义。

甲状腺乳头状癌是发病率增长最快的恶性肿瘤，其中甲状腺微小乳头状癌（PTMC）占50%以上。大多数PTMC具有惰性甚至自限性病程。因此，PTMC的过度诊断及由此导致的过度治疗现象受到广泛而持续的关注。近年来，对低侵袭性PTMC实施主动监测的治疗策略逐渐被接受。PTMC的侵袭性直接影响治疗方式的选择。为实现术前精准预判PTMC侵袭性，本项目在收集大量PTMC多模态超声数据及临床病理资料的基础上，开展分子病理学实验，从PTMC侵袭性出发，向因果两个方向探索，重点进行了如下工作：（1）研究了PTMC侵袭性相关的临床病理特征及多模态超声参数，细化了测量方式，肯定了部分参数对预测PTMC生物学行为的潜在价值；（2）联合应用多模态超声成像预测PTMC侵袭性，提出应用甲状腺结节分类系统评估PTMC侵袭性，评估流程简单，易于在临床实践中推广；（3）探寻PTMC潜在侵袭性分子标志物，否定了部分既往热门的分化型甲状腺癌侵袭性分子标志物对预测PTMC侵袭性的应用价值，同时提出了miR-221，Ki-67等作为PTMC侵袭性标志物的可行性；（4）寻求PTMC侵袭性相关超声征象的成因，并重点围绕lncRNA GAS5发挥ceRNA作用及其对PTMC侵袭性的影响，探究PTMC高侵袭性的内在分子病理学机制。本项目从宏观和微观层面探究PTMC侵袭性相关特征，为术前预判PTMC侵袭性奠定理论及应用基础，有助于无创化评估PTMC侵袭性并制定个体化治疗方案，为解决PTMC过度治疗问题提供了新的视角；另一方面，项目组对侵袭性兴趣分子进行深入探索，深化对侵袭性相关多模态超声参数的理解，有望为未来PTMC精准靶向干预提供理论依据。基于上述研究，本项目已发表SCI收录的国际期刊文章1篇，国内核心期刊文章3篇。已培养了博士研究生3名，硕士研究生4名。