肺癌作为全球范围内癌症相关死亡的主要原因，2022年癌症数据显示肺癌发病率和死亡率居于首位，对人类健康构成了巨大威胁。非小细胞肺癌（NSCLC）作为肺癌的主要亚型，约占所有肺癌病例的85%，其治疗手段包括手术、化学药物治疗、放射治疗、免疫治疗和靶向治疗。放射治疗作为肺癌治疗的重要手段之一，被用于肺癌治疗的各个阶段。然而，由于NSCLC患者对放疗的敏感性存在差异，部分患者因肿瘤细胞的辐射抵抗而降低治疗效果。因此，放疗增敏研究始终是NSCLC治疗的重要方向。此外，近年来，分子靶向治疗的出现使NSCLC的治疗也取得了显著进展，但靶向药物的耐药性问题日益凸显，需要提供新的靶向治疗策略。因此，本文以非小细胞肺癌为研究对象，为提高肿瘤放疗敏感性和靶向治疗的有效性，我们筛选新的治疗靶点，并揭示NSCLC细胞对治疗产生抵抗的分子机制，为临床治疗策略提供潜在靶点和科学依据。本研究以此开展了两部分工作：

        第一部分研究集中于NRF1对NSCLC细胞辐射敏感性的影响及作用机制。NRF1作为核转录因子，参与调控多种细胞过程，包括氧化应激、细胞代谢和蛋白酶体调节等。研究发现，NRF1在电离辐射（IR）条件下，能够响应细胞的DNA损伤应答，促进细胞G2期阻滞，并通过调节RAD51蛋白稳定性，促进同源重组修复（HR）。重要的是，NRF1在NSCLC中的高表达与患者不良预后正相关，提示NRF1可以作为一个新的潜在靶点，用于提高NSCLC细胞的辐射敏感性。

       第二部分研究则聚焦于Kremen2蛋白在NSCLC发展中的作用及分子机制。Kremen2是一种单次跨膜结构蛋白，研究证明其能够参与胚胎发育和骨形成等多种生理过程。本研究发现，Kremen2在NSCLC患者肿瘤组织中高表达，并与不良预后呈正相关。此外，Kremen2的过表达促进了NSCLC细胞的增殖和迁移能力。机制上，Kremen2通过与SOCS3相互作用，阻断泛素依赖的EGFR降解，从而维持EGFR介导的肿瘤信号通路，发挥其致瘤作用。

总之，本论文深入研究了NRF1和Kremen2在NSCLC中的作用机制，以NRF1和Kremen2两个分子为切入点，在NSCLC治疗中寻找新的干预靶点，为开发新的治疗策略提供了理论基础。针对NRF1的调控策略可能有助于增强NSCLC放疗的敏感性，而针对Kremen2的干预可能有助于抑制NSCLC的生长和转移。未来的研究需要进一步验证这些分子靶点在临床治疗中的有效性和安全性，以期为NSCLC患者带来更为有效的治疗策略。

Lung cancer is among the leading causes of cancer-related death for both men and women worldwide. Cancer statistics for 2022 show that lung cancer ranks in the top two cancers for both incidence and mortality, which is a great threat to human health. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 85% of all lung cancer cases. Current treatments for NSCLC include surgery, chemotherapy, radiotherapy, immunotherapy and targeted therapy. Radiotherapy, as an important modality used for the treatment of lung cancer, is used in all stages of lung cancer treatment. Despite significant advances in radiotherapy, tumor radioresistance remain one of the major obstacles to successful treatment with radiotherapy. Therefore, the identification of novel therapeutic targets to enhance the efficacy of radiotherapy represents a pivotal area of investigation in the field of NSCLC treatment. In addition, the advent of targeted therapies has led to notable advancements in the treatment of NSCLC, but the issue of resistance to targeted drugs is gaining prominence. Consequently, novel strategies are required to address or postpone the onset of radioresistance. Thus, focusing on NSCLC as a subject of investigation, we conducted a screening for potential therapeutic targets to enhance the tumor sensitivity to radiotherapy and the efficacy of targeted therapy, elucidating the underlying molecular mechanisms responsible for the resistance of NSCLC cells to treatment, so as to provide potential targets and scientific basis for clinical treatment strategies. As follows, two parts of work were carried out in this study.

        The first part of the study focused on the effect and mechanism of NRF1 on the radiosensitivity of NSCLC cells. NRF1, as a nuclear transcription factor, is involved in the regulation of a variety of cellular processes, including oxidative stress, cellular metabolism and proteasome regulation. We found that NRF1 was able to respond to the cellular DNA damage response under ionizing radiation (IR) conditions, promote G2 cell cycle arrest, and reduce tumor cell radiosensitivity by regulating RAD51 protein stability and promoting homologous recombination repair (HR). Importantly, the high expression of NRF1 in NSCLC was positively correlated with poor patient prognosis, suggesting that NRF1 could be used as a new potential target for enhancing the radiosensitivity of NSCLC cells.

       We investigated the role and molecular mechanism of Kremen2 in the development of NSCLC in the second part of the study. Kremen2 is a single transmembrane structural protein, which has been demonstrated to participate in a variety of physiological processes such as embryonic development and bone formation. We found Kremen2 was highly expressed in tumor tissues from NSCLC patients and associated with poor prognosis. Moreover, the overexpression of Kremen2 promoted the proliferation and migration ability of NSCLC cells. The mechanism by which Kremen2 exerts its tumorigenic effects is through its interaction with SOCS3, which blocks ubiquitin-dependent EGFR degradation, thereby maintaining the activation of EGFR-mediated tumor signaling pathway.

In conclusion, this study conducted a comprehensive investigation into the role and mechanism of NRF1 and Kremen2 in NSCLC. The identification of NRF1 and Kremen2 as potential targets for intervention in NSCLC therapy serves as a theoretical basis for the development of novel therapeutic strategies. Targeting NRF1 has the potential to improve the efficacy of NSCLC radiotherapy, while interventions aimed at Kremen2 may impede the progression and metastasis of NSCLC. Future research is necessary to validate the effectiveness and safety of these molecular targets in clinical practice, with the ultimate goal of advancing more efficient therapeutic modalities for NSCLC patients.