Department of lung transplantation, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310009, China.
Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214000, China.
Respir Res. 2024 Oct 5;25(1):362. doi: 10.1186/s12931-024-02989-7.
The prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression.
Four GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells.
Through bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-β1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts.
Our findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC.
特发性肺纤维化（IPF）患者中非小细胞肺癌（NSCLC）的发病率显著升高。分泌磷蛋白 1（SPP1）参与多种生理过程，包括肿瘤发生和器官纤维化，在 IPF 和 NSCLC 的交叉点上具有模糊的作用。我们的研究旨在阐明 SPP1 在 IPF 发病机制中的功能及其对 NSCLC 进展的后续影响。
分析了四个 GEO 数据集以找到共同差异基因，并使用 TCGA 数据库分析预后。通过 TIMER 数据库分析免疫浸润。检查人肺组织、IPF 成纤维细胞和 BLM 诱导的小鼠肺纤维化模型中的 SPP1 表达。结合 SPP1 基因增益和缺失功能、qRT-PCR、Western blot、EdU 和 CCK-8 实验，评估 SPP1 在 IPF 进展中的作用和机制。通过共培养 IPF 成纤维细胞和 NSCLC 细胞检测 SPP1 对 NSCLC 的影响。
通过生物信息学分析，我们观察到 IPF 和 NSCLC 患者数据集中 SPP1 的显著过表达，与 NSCLC 中癌症相关成纤维细胞的免疫浸润增强相关。在 IPF 患者的肺组织样本和博莱霉素诱导的小鼠模型中检测到 SPP1 水平升高，部分与α-平滑肌肌动蛋白共定位。SPP1 敲低抑制 TGF-β1 诱导的成纤维细胞向肌成纤维细胞分化和 IPF 成纤维细胞增殖。相反，SPP1 过表达通过 PI3K/Akt/mTOR 通路促进 IPF 成纤维细胞增殖。此外，IPF 成纤维细胞促进 NSCLC 细胞增殖并激活 PI3K/Akt/mTOR 通路；这些作用在 IPF 成纤维细胞中 SPP1 敲低时减弱。
我们的研究结果表明，SPP1 作为一种促进纤维化和肿瘤发生的分子发挥作用，使其成为管理 IPF 和 NSCLC 同时发生的有前途的治疗靶点。
