酪氨酸磷酸酶SHP2协同锚定蛋白GAB1调控甲状腺癌恶性进展的机制研究

Recently, the incidence of thyroid cancer increases dramatically. There are several aggressive forms of thyroid cancer with extremely poor prognosis and higher mortality. However, for the exact progression mechanisms of thyroid cancer remain unclear, the stratification diagnosis of thyroid cancer patients is hampered by the shortage of highly efficient biomarkers. It has been shown that reversible tyrosine phosphorylation plays a key role in the pathogenesis of thyroid cancer. The SHP2, a non-receptor tyrosine phosphatase coding by the oncogenic PTPN11, is acting as a multi-functional phosphatase dependent to its combination with different scaffolding proteins. Our previously retrospective study showed that SHP2 was highly expressed in all types of thyroid cancer, while GAB1 was only highly expressed in aggressive thyroid cancer. And the dual-expression of GAB1 and SHP2 was significantly relative to the recurrence of thyroid cancer. Furthermore, the forced expression of GAB1 promoted the proliferation and migration of thyroid cancer cells. It was suggested that the dual-expression of GAB1 and SHP2 played a key role in the progress of thyroid cancer，and it was a potential biomarker for the prognostic prediction of thyroid cancer patients. Herein, in this project, we intend to disclose the roles of GAB1-SHP2 in regulating the progression thyroid cancer and the correlation between the expression of the complex and prognosis of patients. And the biological significance and mechanism will be further elucidated by using molecular techniques and SHP2 mutation knock-in mice. Our research can provide novel theoretical basis and experimental support for the stratification diagnosis of thyroid cancer patients.

近年来甲状腺癌(TC)发病率飙升,部分TC恶性程度高,预后差。由于此类TC恶性进展机制不明,缺乏有效分子标记物,是依据风险度分层诊疗TC的主要障碍。可逆酪氨酸磷酸化调控在TC恶性进展中具有关键意义,原癌基因PTPN11编码SHP2是酪氨酸磷酸酶家族成员,生物学功能广泛,与不同锚定蛋白形成的复合物构成其精准时空调控的分子基础。临床数据显示TC组织SHP2普遍强阳性表达,与其上游锚定蛋白GAB1的阳性共表达（SHP2+/GAB1+）和预后不良相关;GAB1上调可促进TC细胞增殖和迁移,提示SHP2/GAB1双阳性特征很可能是TC预警恶性的关键分子事件。基于此,本研究将聚焦SHP2协同GAB1调控TC恶性进程机制,明确双阳性患者病理特征及与TC恶性进展、预后的相关性,采用分子技术结合转基因小鼠阐明GAB1-SHP2信号调控TC恶性行为的生物学意义及机制,预期为TC分层诊疗提供理论基础与实验依据。

近年来甲状腺癌发病率呈逐年上升趋势，部分甲状腺癌恶性程度高，预后差，但恶性进展机制不明。项目组前期明确酪氨酸磷酸酶SHP2可与锚定蛋白GAB1形成复合物调控肿瘤恶性进展。本项目基于此，聚焦高风险甲状腺癌病理特征，深入诠释了SHP2-GAB1信号调控肿瘤增殖、侵袭等肿瘤恶性进展相关生物学作用及分子机制。首先，收集甲状腺癌患者样本，数据分析显示SHP2、GAB1阳性表达与其临床预后显著相关，在临床水平证实SHP2-GAB1表达上调是甲状腺癌的高危因素。随后，体外研究发现，GAB1在恶性程度较高的未分化性甲状腺癌（ATC）细胞系中高表达，且过表达GAB1可促进甲状腺癌细胞迁移和侵袭。体内实验显示敲降GAB1可抑制ATC细胞皮下移植瘤和原位瘤模型生长，且GAB1表达水平与肿瘤大小呈正相关。进一步研究发现SHP2-GAB1信号促进甲状腺细胞迁移和侵袭的机制与PI3K通路激活相关，且该通路激活后可正向调控ATC细胞中干性指标MDR1的表达，在分子机制水平阐明SHP2-GAB1信号在甲状腺癌恶性进展中的作用。综上所述，本研究探索SHP2协同GAB1调控甲状腺癌恶性进展及高危因素，阐明GAB1-SHP2信号调控甲状腺癌恶性行为的生物学机制，预期为甲状腺癌分层诊疗提供理论基础与实验依据。