吉西他滨是局部晚期或转移性胰腺导管腺癌 (PDAC) 患者的一线治疗选择。然而，癌细胞经常对吉西他滨产生耐药性，这给治疗这种侵袭性疾病带来了重大挑战。在本研究中，我们重点分析了三叶因子 1 (TFF1) 在 PDAC 吉西他滨耐药中的作用。 PDAC TCGA 和细胞系数据集的分析表明 TFF1 在吉西他滨耐药的经典亚型中富集，并表明 TFF1 表达与吉西他滨治疗敏感性之间呈负相关。 PDAC 细胞中 TFF1 的基因消除增强了它们在体外和体内肿瘤异种移植物中对吉西他滨治疗的敏感性。生化研究表明，TFF1 通过增强干性、增加癌细胞的迁移能力和诱导抗凋亡基因，有助于吉西他滨耐药。我们进一步开展研究来预测可能发挥 TFF1 介​​导的吉西他滨耐药性的受体。使用 BioLuminate 软件进行的蛋白质-蛋白质对接研究表明，TFF1 与趋化因子受体 CXCR4 结合，这得到了使用 SPR 研究对 TFF1 和 CXCR4 进行实时结合分析的支持。外源添加 TFF1 通过 pAkt/pERK 轴增加了 PDAC 细胞的增殖和迁移，而用 CXCR4 特异性拮抗剂 AMD3100 治疗可以消除这种情况。总体而言，本研究证明了 TFF1-CXCR4 轴在赋予 PDAC 细胞吉西他滨耐药特性方面的贡献。版权所有 © 2024。由 Elsevier B.V. 出版。

Gemcitabine is the first-line treatment option for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). However, the frequent adoption of resistance to gemcitabine by cancer cells poses a significant challenge in treating this aggressive disease. In this study, we focused on analyzing the role of trefoil factor 1 (TFF1) in gemcitabine resistance in PDAC. Analysis of PDAC TCGA and cell line datasets indicated an enrichment of TFF1 in the gemcitabine-resistant classical subtype and suggested an inverse correlation between TFF1 expression and sensitivity to gemcitabine treatment. The genetic ablation of TFF1 in PDAC cells enhanced their sensitivity to gemcitabine treatment in both in vitro and in vivo tumor xenografts. The biochemical studies revealed that TFF1 contributes to gemcitabine resistance through enhanced stemness, increasing migration ability of cancer cells, and induction of anti-apoptotic genes. We further pursued studies to predict possible receptors exerting TFF1-mediated gemcitabine resistance. Protein-protein docking investigations with BioLuminate software revealed that TFF1 binds to the chemokine receptor CXCR4, which was supported by real-time binding analysis of TFF1 and CXCR4 using SPR studies. The exogenous addition of TFF1 increased the proliferation and migration of PDAC cells through the pAkt/pERK axis, which was abrogated by treatment with a CXCR4-specific antagonist AMD3100. Overall, the present study demonstrates the contribution of the TFF1-CXCR4 axis in imparting gemcitabine resistance properties to PDAC cells.Copyright © 2024. Published by Elsevier B.V.