第一部分：目的：探讨脉管瘤栓对pT1N0M0期肺腺癌患者术后无复发生存期的影响。方法：回顾性分析2014年1月至2017年6月中国医学科学院肿瘤医院胸外科442例行手术治疗的pT1N0M0肺腺癌患者的临床病理及随访资料，男203例，女239例。根据脉管瘤栓状态将患者分为两组，即脉管瘤栓（-）（367例）和脉管瘤栓（+）（75例）组；并根据国际抗癌联盟（Union for International Cancer Control, UICC）和美国联合癌症联合会（American Joint Committee on Cancer, AJCC）第8版肺癌术后病理肿瘤大小T分期进行分层分析，其中pT1a（pT≤1cm，75例）、pT1b（1cm＜pT≤2cm，245例）、pT1c（2cm＜pT≤3cm，122例）和pT1b/c（1cm＜pT≤3cm，367例）。采用Cox单因素和多因素比例风险模型和Kaplan-Meier（K-M）曲线分析脉管瘤栓对纳入人群的无复发生存期的影响。结果：脉管瘤栓（+）组的复发率高于脉管瘤栓（-）组（25.3%比6.3%，P < 0.001）。基于pT分层的单因素和多因素Cox回归分析结果显示，在pT1、pT1b和pT1c分层中，脉管瘤栓（+）患者的复发风险比脉管瘤栓（-）患者分别高3.711、3.808和3.421倍（95% CI：1.783~7.726、1.282~11.311和1.316~8.892；P < 0.001、0.016和0.012）。pT1、pT1b、pT1c和pT1b/c中脉管瘤栓（+）组与脉管瘤栓（-）组患者的无复发生存期差异均具有显著统计学意义，平均无复发生存期分别为[（73.0±3.5）比（91.3±0.9）个月，P < 0.001]、[（67.4±4.0）比（91.5±1.2）个月，P = 0.026] 、[（69.7±4.7）比（85.3±2.1）个月，P = 0.001]和[（72.8±3.6）比（91.0±1.0）个月，P < 0.001]。结论：对于ⅠA期肺腺癌患者，脉管瘤栓（+）患者复发率更高，无复发生存期更差。

第二部分：肺癌是世界范围内死亡率排名第一的恶性肿瘤，探索发病新机制进而开发治疗新策略是提高疗效的重要途径。课题组前期研究基础证实野生型IDH1在肺癌组织中特异性高表达，促进肿瘤生长，与肺癌预后不良显著相关。进一步的研究发现：①野生型IDH1增强了丝氨酸/甘氨酸从头合成途径；②野生型IDH1与PHGDH相互作用阻碍了泛素E3连接酶Parkin介导的PHGDH K330位泛素化和蛋白降解；③野生型IDH1与FXR1蛋白相互作用阻碍了泛素E3连接酶Parkin介导的FXR1泛素化和蛋白降解，从而促进PSAT1表达；④野生型IDH1-丝氨酸/甘氨酸从头合成途径调控轴带来的代谢重编程维持了非小细胞肺癌干细胞特性。但其中部分分子机制尚不清晰，因此本研究进一步通过实验揭示了：①野生型IDH1与FXR1蛋白相互作用阻碍了泛素E3连接酶Parkin介导的FXR1 K21位泛素化和蛋白降解；②FXR1作为RNA结合蛋白与PSAT1 mRNA相互作用维持了其稳定性，从而促进了丝氨酸/甘氨酸从头合成途径，得以维持非小细胞肺癌干细胞特性。以上工作完善了野生型IDH1-丝氨酸/甘氨酸从头合成途径调控轴的分子机制，并进一步证实野生型IDH1通过增强丝氨酸/甘氨酸合成维持非小细胞干细胞特性，为肺癌诊疗提供一种新的思路。

Part 1: Purpose: To investigate the influence of vascular invasion on postoperative recurrence-free survival in patients with stage ⅠA lung adenocarcinoma. Methods: From January 2015 to January 2018, the clinicopathological and follow-up data of 442 patients with stage pT1N0M0 lung adenocarcinoma who underwent surgery in the Department of Thoracic Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, were retrospectively analyzed. There were 203 males and 239 females. Patients were divided into two groups according to the status of vascular invasion, namely, vascular invasion (-) (367 cases) and vascular invasion (+) (75 cases) group. And the stratified analysis was completed according to the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) 8th edition tumor size T-stage (pT) of lung cancers, including pT1a (pT≤1cm, 75 cases), pT1b (1cm<pT≤2cm, 245 cases), pT1c (2cm<pT≤3cm, 122 cases) and pT1b/c (1cm<pT≤3cm, 367 cases). Cox univariate and multivariate proportional hazards models and Kaplan-Meier (K-M) curves were used to analyze the influence of vascular invasion on the recurrence-free survival of the included population. Results: The recurrence rate of the vascular invasion (+) group was higher than that of the vascular invasion (-) group (25.3% vs 6.3%, P < 0.001). The results of univariate and multivariate Cox regression analysis based on pT stratification showed that in pT1, pT1b and pT1c stratification, the recurrence risk of patients with vascular tumor thrombus (+) was 3.711, 3.711, 3.808 and 3.421 times (95% CI: 1.783~7.726, 1.282~11.311 and 1.316~8.892; P < 0.001, 0.016 and 0.012). In pT1, pT1b, pT1c, and pT1b/c, there were significant differences in recurrence-free survival between the vascular invasion (+) group and the vascular invasion (-) group, and the average recurrence-free survival was [(73.0±3.5) vs (91.3±0.9) months, P < 0.001], [(67.4±4.0) vs (91.5±1.2) months, P=0.026], [(69.7±4.7) vs (85.3±2.1) months, P = 0.001] and [(72.8±3.6) vs (91.0±1.0) months, P < 0.001]. Conclusion: For patients with stage ⅠA lung adenocarcinoma, patients with vascular invasion (+) had a higher recurrence rate and worse recurrence-free survival.

Part 2: Lung cancer is the malignant tumor with the highest mortality rate in the world. Exploring new mechanisms of pathogenesis and developing new treatment strategies are important ways to improve efficacy. The previous research of the research group has confirmed that wild-type IDH1 is specifically highly expressed in lung cancer tissues, promotes tumor growth, and is significantly related to poor prognosis of lung cancer. Further studies found that: ①Wild-type IDH1 enhanced the serine/glycine de novo synthesis pathway; ②The interaction between wild-type IDH1 and PHGDH hindered the ubiquitin E3 ligase Parkin-mediated PHGDH K330 ubiquitination and protein degradation; ③Wild-type The interaction between IDH1 and FXR1 protein hinders the ubiquitin E3 ligase Parkin-mediated FXR1 ubiquitination and protein degradation, thereby promoting the expression of PSAT1; ④The maintenance of metabolic reprogramming brought about by the wild-type IDH1-serine/glycine de novo synthesis pathway regulation axis Characteristics of non-small cell lung cancer stem cells. However, some of the molecular mechanisms are still unclear, so this study further revealed through experiments: ①The interaction between wild-type IDH1 and FXR1 protein hinders the ubiquitin E3 ligase Parkin-mediated ubiquitination and protein degradation of FXR1 K21; ②FXR1 acts as RNA-binding protein interacts with PSAT1 mRNA to maintain its stability, thereby promoting the de novo serine/glycine synthesis pathway to maintain non-small cell lung cancer stem cell properties. The above work perfected the molecular mechanism of wild-type IDH1-serine/glycine de novo synthesis pathway regulation axis and further confirmed that wild-type IDH1 maintains the characteristics of non-small cell stem cells by enhancing serine/glycine synthesis, providing a new idea for the diagnosis and treatment of lung cancer.