FBXW7非降解结合PTPN12调控非小细胞肺癌的发生发展

Abnormal tyrosine phosphorylation is one of the most important impetuses that drive malignant tumor transformation. As a newly identified regulator actively involved in protein phosphorylation networks, protein tyrosine phosphatase PTPN12 is correlated with the pathogenesis of various tumors, yet its functional role and the underlying mechanism in non-small cell lung cancer (NSCLC) remain uncertain. Our previous study discovered that PTPN12 could inhibit cell proliferation, metastasis, as well as phosphorylation of several receptor tyrosine kinases (RTKs). Meanwhile, its phosphatase activity is also regulated by FBXW7 mediated ubiquitination. We postulate that PTPN12 may exert tumor-suppressing effects through inhibiting RTK-induced tyrosine phosphorylation in NSCLC, which, is further enhanced by FBXW7 activity. Taken together, these three molecules co-regulate tumorigenesis and tumor progression of NSCLC. To validate the preliminary data and confirm our hypotheses, we plan to clarify the following points at molecular, cellular, mouse and clinical levels successively: 1. To verify the suppressor roles of PTPN12 in NSCLC；2.To elucidate the regulatory mechanism of PTPN12 in NSCLC development and progression via interacting with RTKs; 3. To unveil the molecular mechanism by which FBXW7 regulates PTPN12 functions; 4. To analyze the clinical significance of FBXW7-PTPN12-RTKs pathway in NSCLC samples to provide novel insights into the molecular diagnosis and targeted therapy in NSCLC.

异常的酪氨酸磷酸化修饰是细胞恶性转化的重要驱动因素之一。PTPN12是新近发现的蛋白质磷酸化网络的重要调控因子，参与多种肿瘤的病理过程，但其在非小细胞肺癌（NSCLC）中的作用及机制尚不清楚。我们前期研究发现PTPN12能抑制NSCLC细胞增殖和迁移并能抑制多种RTKs的磷酸化，同时其自身活性受到FBXW7的泛素化修饰调控。我们推测PTPN12通过抑制RTKs在NSCLC中发挥抑癌作用，而FBXW7增强PTPN12的抑癌功能，三者共同调节NSCLC的发生发展。本项目拟在前期研究基础上，从分子、细胞、小鼠和临床水平，①明确PTPN12在NSCLC中的作用； ②阐明PTPN12通过RTKs调控NSCLC发生发展的机制；③ 阐明FBXW7调控PTPN12的分子基础及作用；④并在NSCLC标本中分析FBXW7-PTPN12-RTKs通路的临床意义，为研发NSCLC诊治的有效靶点提供思路。

异常的酪氨酸磷酸化修饰是细胞恶性转化的重要驱动因素之一。PTPN12是新近发现的蛋白质磷酸化网络的重要调控因子，参与多种肿瘤的病理过程，但其在非小细胞肺癌（NSCLC）中的作用及机制尚不清楚，有研究报道PTPN12在NSCLC中失表达，而其失表达的机制亦尚远未阐明。本项目在前期研究基础上，从分子、细胞、小鼠和临床水平系统研究了PTPN12在NSCLC中的作用、作用机制及其在NSCLC中失表达的机制。研究结果显示：1）PTPN12在体外可以显著抑制NSCLC细胞的增殖、侵袭和迁移；在体内能够抑制NSCLC细胞成瘤和转移能力； 2）PTPN12通过抑制MAPK和AKT/mTOR信号通路发挥对NSCLC发生发展的抑制作用； 3）FBXW7通过抑制EZH2-H3K27me3正向调控PTPN12的表达，NSCLC中FBXW7缺失导致PTPN12表达下调，加速NSCLC的发生和进展。本项目为进一步深入理解NSCLC发生发展的分子机制奠定重要的理论基础，并为NSCLC的有效防治提供了新的靶点和思路。