Gong Han, Zhang Peihe, Liu Qiang, Tian Yuxuan, Chen Fuxin, Qian Siyi, Tu Chaofeng, Tan Yueqiu, Hu Xingming, Zhang Bin
The 1st Department of Thoracic Surgery of Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 4100013, China.
Molecular Biology Research Center and Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
NPJ Precis Oncol. 2024 Aug 1;8(1):169. doi: 10.1038/s41698-024-00658-y.
Lung adenocarcinoma (LUAD) is a leading cause of cancer mortality, with many patients facing poor prognosis, particularly those with metastatic or drug-resistant tumors. Homologous recombination genes (HRGs) are crucial in tumor progression and therapy resistance, but their clinical significance in LUAD is not well understood. In this study, we systematically characterize key HRGs in LUAD patients, identifying two distinct HR subtypes associated with different outcomes and biological functions. We establish a 5-gene scoring system (XRCC2, RAD51, BRCA1, FANCA, and CHEK1) that reliably predicts patient outcomes and immunotherapy responses in LUAD. Bioinformatics analysis and clinical validation highlight XRCC2 as a crucial biomarker in LUAD. Functional investigations through in vivo and in vitro experiments reveal the role of XRCC2 in promoting lung cancer migration and invasion. Mechanistically, XRCC2 stabilizes vimentin (VIM) protein expression through deubiquitylation. We predict c-MYC as a potential regulator of XRCC2 and demonstrate that inhibiting c-MYC with compound 10058-F4 reduces XRCC2 and VIM expression. Preclinical studies show the synergistic inhibition of metastasis in vivo when combining 10058-F4 with doxorubicin (Dox). Our findings present a potential personalized predictive tool for LUAD prognosis, identifying XRCC2 as a critical biomarker. The c-Myc-XRCC2-VIM axis emerges as a promising therapeutic target for overcoming lung metastasis. This study provides valuable insights into LUAD, proposing a prognostic tool for further clinical validation and unveiling a potential therapeutic strategy for combating lung metastasis by targeting c-Myc-XRCC2-VIM.
肺腺癌（LUAD）是癌症死亡的主要原因，许多患者预后较差，尤其是那些患有转移性或耐药性肿瘤的患者。同源重组基因（HRGs）在肿瘤进展和治疗耐药性中至关重要，但其在LUAD中的临床意义尚未得到充分了解。在本研究中，我们系统地描述了LUAD患者中的关键HRGs，确定了两种与不同结果和生物学功能相关的不同HR亚型。我们建立了一个5基因评分系统（XRCC2、RAD51、BRCA1、FANCA和CHEK1），该系统能够可靠地预测LUAD患者的预后和免疫治疗反应。生物信息学分析和临床验证突出了XRCC2作为LUAD中的关键生物标志物。通过体内和体外实验进行的功能研究揭示了XRCC2在促进肺癌迁移和侵袭中的作用。从机制上讲，XRCC2通过去泛素化稳定波形蛋白（VIM）的蛋白表达。我们预测c-MYC是XRCC2的潜在调节因子，并证明用化合物10058-F4抑制c-MYC可降低XRCC2和VIM的表达。临床前研究表明，将10058-F4与阿霉素（Dox）联合使用时，可在体内协同抑制转移。我们的研究结果为LUAD预后提供了一种潜在的个性化预测工具，确定XRCC2为关键生物标志物。c-Myc-XRCC2-VIM轴成为克服肺转移的有前景的治疗靶点。本研究为LUAD提供了有价值的见解，提出了一种预后工具以供进一步临床验证，并揭示了一种通过靶向c-Myc-XRCC2-VIM对抗肺转移的潜在治疗策略。
