Hua Qian, Wang Ning, Wang Dan, Wen Jun, Mi Baoming
Department of Nuclear Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, Jiangsu, China.
Department of Radiology,, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, 215004, Jiangsu, China.
Ann Nucl Med. 2025 May 11. doi: 10.1007/s12149-025-02056-1.
Cisplatin-based concurrent chemotherapy is considered first-line treatment for advanced NSCLC. In this study, the role of Ga-FAPI in visualizing chemotherapy resistance and the regulatory mechanisms which CAFs influence chemoresistance of NSCLC was evaluated.
The CAFs were isolated form fresh NSCLC tissue, and the expression of FAP was evaluated by qRT-PCR and western blotting. Ga-FAPI micro-PET/CT was performed to visualize CAFs distribution and quantity in vivo. A cytokine array was conducted to analyze the secretion of HGF. The expression of LINC01123 was detected by overlapping high-throughput sequencing results with the analysis of the GEO database (GSE43493). Finally, the interaction between LINC01123 and β-catenin was assessed using RNA pull-down and RIP techniques.
In this study, we employed Ga-FAPI micro-PET/CT to quantify the number of CAFs and visualize the different uptake between cisplatin sensitive and resistant NSCLC xenograft models. The biological role of CAFs in cisplatin treatment for NSCLC was evaluated through functional experiments in vitro and in vivo. Functional assay demonstrated that CAFs secrete HGF which upregulates the expression of LINC01123 in NSCLC cells. LINC01123 directly binds to β-catenin and enhances its transcription activity. The activated HGF/LILNC01123/β-catenin signaling-mediated crosstalk between CAFs and tumor cells drives the chemoresistance of NSCLC.
Dysregulated activation of the HGF/LINC01123/β-catenin cascade represents a pivotal pathway through which CAFs interact with NSCLC cells, which enhancing the role of Ga-FAPI to visualize chemotherapy resistance in patients.
基于顺铂的同步化疗被认为是晚期非小细胞肺癌（NSCLC）的一线治疗方法。在本研究中，评估了镓标记的成纤维细胞激活蛋白抑制剂（Ga-FAPI）在可视化化疗耐药性中的作用以及癌相关成纤维细胞（CAFs）影响NSCLC化疗耐药性的调控机制。
从新鲜的NSCLC组织中分离出CAFs，并通过定量逆转录聚合酶链反应（qRT-PCR）和蛋白质免疫印迹法评估成纤维细胞激活蛋白（FAP）的表达。进行Ga-FAPI微型正电子发射断层扫描/计算机断层扫描（micro-PET/CT）以可视化体内CAFs的分布和数量。进行细胞因子阵列分析以检测肝细胞生长因子（HGF）的分泌。通过将高通量测序结果与基因表达综合数据库（GEO数据库，GSE43493）分析结果重叠来检测LINC01123的表达。最后，使用RNA下拉和RNA免疫沉淀（RIP）技术评估LINC01123与β-连环蛋白之间的相互作用。
在本研究中，我们采用Ga-FAPI micro-PET/CT来量化CAFs的数量，并可视化顺铂敏感和耐药NSCLC异种移植模型之间不同的摄取情况。通过体外和体内功能实验评估了CAFs在NSCLC顺铂治疗中的生物学作用。功能分析表明，CAFs分泌HGF，其上调NSCLC细胞中LINC01123的表达。LINC01123直接与β-连环蛋白结合并增强其转录活性。激活的HGF/LILNC01123/β-连环蛋白信号介导的CAFs与肿瘤细胞之间的串扰驱动了NSCLC的化疗耐药性。
HGF/LINC01123/β-连环蛋白级联的失调激活代表了CAFs与NSCLC细胞相互作用的关键途径，这增强了Ga-FAPI在可视化患者化疗耐药性方面的作用。
