Yu Juncheng, Lu Xiao, Zhou Dong, Zhang Jiao, Deng Xufeng, Liu Xiaobing, Wang Kai, Liao Shuangqing, Zheng Hong, Dai Jigang
Department of Thoracic Surgery, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
Funct Integr Genomics. 2025 Jun 6;25(1):121. doi: 10.1007/s10142-025-01629-7.
Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide, with limited response rates and resistance to targeted therapies and immunotherapies. Pin1, a phosphorylation-specific peptidyl-prolyl isomerase, has been implicated in multiple oncogenic pathways; however, its role in LUAD is not fully understood. We conducted an integrative analysis using public datasets (TCGA, GEO, HPA), LUAD tissue microarrays, malignant pulmonary nodule specimens, and cell line models to investigate the expression and function of PIN1 in LUAD. Functional assays, immunohistochemistry, and in vivo xenograft models were employed to validate the biological effects of PIN1 in LUAD progression and treatment response. PIN1 expression was significantly downregulated in LUAD tissues compared to adjacent normal lung tissues. High PIN1 expression was associated with improved overall survival, increased immune cell infiltration, and enhanced response to immunotherapy. Overexpression of PIN1 inhibited proliferation and migration while promoting apoptosis of LUAD cells in vitro and in vivo. Mechanistically, high PIN1 expression activated downstream pAKT and pMAPK signaling, potentially contributing to EGFR-TKI resistance despite unchanged pEGFR levels. Moreover, functional enrichment analysis and immune profiling revealed that PIN1 is positively associated with antitumor immune responses in LUAD, contrasting its immunosuppressive role in other cancers. PIN1 exhibits tumor-suppressive activity in LUAD and may serve as a promising biomarker for prognosis and therapeutic response. These findings underscore the context-dependent role of PIN1 and support further exploration of its mechanistic involvement in LUAD immunobiology and targeted therapy resistance.
肺腺癌（LUAD）仍然是全球癌症相关死亡的主要原因，对靶向治疗和免疫治疗的反应率有限且存在耐药性。Pin1是一种磷酸化特异性肽基脯氨酰异构酶，已被证明参与多种致癌途径；然而，其在LUAD中的作用尚未完全明确。我们使用公共数据集（TCGA、GEO、HPA）、LUAD组织芯片、恶性肺结节标本和细胞系模型进行综合分析，以研究PIN1在LUAD中的表达和功能。采用功能测定、免疫组织化学和体内异种移植模型来验证PIN1在LUAD进展和治疗反应中的生物学效应。与相邻正常肺组织相比，PIN1在LUAD组织中的表达显著下调。高PIN1表达与总体生存率提高、免疫细胞浸润增加以及对免疫治疗的反应增强相关。PIN1过表达在体外和体内均抑制LUAD细胞的增殖和迁移，同时促进其凋亡。机制上，高PIN1表达激活下游pAKT和pMAPK信号通路，尽管pEGFR水平未改变，但可能导致EGFR-TKI耐药。此外，功能富集分析和免疫图谱显示，PIN1与LUAD中的抗肿瘤免疫反应呈正相关，这与其在其他癌症中的免疫抑制作用形成对比。PIN1在LUAD中表现出肿瘤抑制活性，可能作为一种有前景的预后和治疗反应生物标志物。这些发现强调了PIN1的背景依赖性作用，并支持进一步探索其在LUAD免疫生物学和靶向治疗耐药性中的机制参与。
