Department of Hepatobiliary and Intestinal Surgery of Hunan Cancer Hospital & the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Histology and Embryology, School of Basic Medical Sciences, Central South University, Changsha 410013, China.
Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Central South University, Changsha, Hunan 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Biomed Pharmacother. 2024 Oct;179:117315. doi: 10.1016/j.biopha.2024.117315. Epub 2024 Aug 16.
Lung cancer represents one of the most prevalent malignant neoplasms, commanding an alarming incidence and mortality rate globally. Non-small cell lung cancer (NSCLC), constituting approximately 80 %-90 % of all lung cancer cases, is the predominant pathological manifestation of this disease, with a disconcerting 5-year survival rate scarcely reaching 10 %. Extensive prior investigations have elucidated that the aberrant expression of X-ray repair cross-complementing gene 2 (XRCC2), a critical meiotic gene intricately involved in the DNA damage repair process, is intimately associated with tumorigenesis. Nevertheless, the precise roles and underlying mechanistic pathways of XRCC2 in NSCLC remain largely elusive. In the present study, we discerned an overexpression of XRCC2 within NSCLC patient tissues, particularly in high-grade samples, when juxtaposed with normal tissues. Targeted knockdown of XRCC2 notably impeded the proliferation of NSCLC both in vitro and in vivo. Comprehensive RNA sequencing and flow rescue assays unveiled that XRCC2 augments the proliferation of NSCLC cells through the down-regulation of FOS expression. Moreover, the c-Myc gene was definitively identified as an XRCC2 transcriptional factor by means of chromatin immunoprecipitation (ChIP) and luciferase reporter assays, whereby pharmacological attenuation of c-Myc expression, in conjunction with Doxorubicin, synergistically curtailed NSCLC cell growth both in vitro and in vivo. Collectively, our findings proffer critical insights into the novel c-Myc-XRCC2-FOS axis in promoting both proliferation and resistance to Doxorubicin in NSCLC cells, thereby extending a promising avenue for potential new diagnostic strategies and therapeutic interventions in NSCLC.
肺癌是最常见的恶性肿瘤之一，在全球范围内发病率和死亡率都很高。非小细胞肺癌（NSCLC）约占所有肺癌病例的 80%-90%，是该病的主要病理表现，5 年生存率令人担忧，仅勉强达到 10%。大量先前的研究已经阐明，X 射线修复交叉互补基因 2（XRCC2）的异常表达与肿瘤发生密切相关，XRCC2 是一个关键的减数分裂基因，参与 DNA 损伤修复过程。然而，XRCC2 在 NSCLC 中的确切作用和潜在的机制途径在很大程度上仍未被揭示。在本研究中，我们发现 NSCLC 患者组织中 XRCC2 表达过度，特别是在高级别样本中，与正常组织相比。靶向敲低 XRCC2 显著抑制了 NSCLC 在体外和体内的增殖。全面的 RNA 测序和流式细胞术挽救实验表明，XRCC2 通过下调 FOS 表达来增强 NSCLC 细胞的增殖。此外，通过染色质免疫沉淀（ChIP）和荧光素酶报告基因实验，确定 c-Myc 基因是 XRCC2 的转录因子，药物抑制 c-Myc 表达与多柔比星联合使用，在体外和体内协同抑制 NSCLC 细胞生长。综上所述，我们的研究结果提供了关于促进 NSCLC 细胞增殖和多柔比星耐药的新型 c-Myc-XRCC2-FOS 轴的重要见解，为 NSCLC 的潜在新诊断策略和治疗干预提供了有希望的途径。
