Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Chemotherapy based on gemcitabine (GEM) remains the first-line drug for patients with advanced PDAC. However, GEM resistance impairs its therapeutic effectiveness. Therefore, identifying effective therapeutic targets are urgently needed to overcome GEM resistance. The clinical significance of Tripartite Motif Containing 29 (TRIM29) was identified by exploring GEO datasets and TCGA database and its potential biological functions were predicted by GSEA analysis. The regulatory axis was established by bioinformatics analysis and validated by mechanical experiments. Then, in vitro and in vivo assays were performed to validate the roles of TRIM29 in PDAC GEM resistance. High TRIM29 expression was associated with poor prognosis of PDAC and functional experiments demonstrated that TRIM29 promoted GEM resistance in PDAC GEM-resistant (GR) cells. Furthermore, we revealed that circRPS29 promoted TRIM29 expression via competitive interaction with miR-770–5p and then activated MEK/ERK signaling pathway. Additionally, both in vitro and in vivo functional experiments demonstrated that circRPS29/miR-770–5p/TRIM29 axis promoted PDAC GEM resistance via activating MEK/ERK signaling pathway. Our results identify the significance of the signaling axis, circRPS29/miR-770–5p/TRIM29-MEK/ERK, in PDAC GEM resistance, which will provide novel therapeutic targets for PDAC treatment.

中文翻译：

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TRIM29 通过 MEK/ERK 途径促进吉西他滨耐药，并受 PDAC 中的 circRPS29/miR-770–5p 轴调节

胰腺导管腺癌（PDAC）是一种高度致命的疾病。基于吉西他滨 (GEM) 的化疗仍然是晚期 PDAC 患者的一线药物。然而，GEM 耐药性损害了其治疗效果。因此，迫切需要确定有效的治疗靶点来克服 GEM 耐药性。通过探索GEO数据集和TCGA数据库确定了Tripartite Motif Containing 29（TRIM29）的临床意义，并通过GSEA分析预测了其潜在的生物学功能。通过生物信息学分析建立调节轴并通过机械实验验证。然后，进行体外和体内测定以验证 TRIM29 在 PDAC GEM 抗性中的作用。 TRIM29 高表达与 PDAC 不良预后相关，功能实验表明 TRIM29 促进 PDAC GEM 抗性 (GR) 细胞中的 GEM 抗性。此外，我们发现circRPS29通过与miR-770-5p竞争性相互作用促进TRIM29表达，然后激活MEK/ERK信号通路。此外，体外和体内功能实验均表明，circRPS29/miR-770-5p/TRIM29轴通过激活MEK/ERK信号通路促进PDAC GEM抵抗。我们的结果确定了信号轴 circRPS29/miR-770–5p/TRIM29-MEK/ERK 在 PDAC GEM 耐药中的重要性，这将为 PDAC 治疗提供新的治疗靶点。