Zhang Shufan, Xu Tianhan, Li Simeng, Tang Liming, Wang Dongmei
Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Nanjing Medical University, Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou 213000, P. R. C.
Technol Cancer Res Treat. 2025 Jan-Dec;24:15330338251344424. doi: 10.1177/15330338251344424. Epub 2025 May 23.
Lung adenocarcinoma remains a significant public health concern, necessitating novel therapeutic approaches. Neuregulin 4 (NRG4), a secreted protein of the epidermal growth factor family, is recognized for its roles in metabolic regulation and anti-inflammatory processes, suggesting therapeutic potential across various diseases. However, its specific function in lung adenocarcinoma progression is not well elucidated. We utilized The Cancer Genome Atlas (TCGA) database to examine correlations between NRG4 expression, epithelial-mesenchymal transition (EMT)-related genes, and overall survival in lung adenocarcinoma patients. The effects of recombinant NRG4 (rNRG4) on cell migration and cancer progression were evaluated through Transwell assays, quantitative PCR, immunofluorescence, and immunohistochemistry. Additionally, a lung adenocarcinoma mouse model (LLC-bearing) was employed to assess the impact of rNRG4 on tumor progression. RNA sequencing of primary tumors was conducted to explore the functional mechanisms underlying rNRG4's effects. Our analysis revealed that NRG4 expression inversely correlates with key molecules involved in cell migration and EMT in lung adenocarcinoma. Treatment with rNRG4 significantly inhibited cell proliferation, migration, EMT, and tumor growth in both in vitro and in vivo models. RNA sequencing indicated that rNRG4 downregulates extracellular matrix (ECM) proteins, and online database analyses confirmed that higher NRG4 expression is associated with reduced ECM levels and improved patient survival. These findings suggest that NRG4 serves as a potential candidate for further investigation for lung adenocarcinoma.
肺腺癌仍然是一个重大的公共卫生问题，需要新的治疗方法。神经调节蛋白4（NRG4）是表皮生长因子家族的一种分泌蛋白，因其在代谢调节和抗炎过程中的作用而受到认可，这表明它在各种疾病中具有治疗潜力。然而，其在肺腺癌进展中的具体功能尚未得到充分阐明。我们利用癌症基因组图谱（TCGA）数据库来研究NRG4表达、上皮-间质转化（EMT）相关基因与肺腺癌患者总生存期之间的相关性。通过Transwell实验、定量PCR、免疫荧光和免疫组织化学评估重组NRG4（rNRG4）对细胞迁移和癌症进展的影响。此外，还采用了肺腺癌小鼠模型（携带LLC）来评估rNRG4对肿瘤进展的影响。对原发性肿瘤进行RNA测序，以探索rNRG4作用的功能机制。我们的分析表明，NRG4表达与肺腺癌中参与细胞迁移和EMT的关键分子呈负相关。在体外和体内模型中，rNRG4治疗均显著抑制细胞增殖、迁移、EMT和肿瘤生长。RNA测序表明，rNRG4下调细胞外基质（ECM）蛋白，在线数据库分析证实，较高的NRG4表达与降低的ECM水平和改善的患者生存率相关。这些发现表明，NRG4是肺腺癌进一步研究的潜在候选对象。
