TRIM29 facilitates gemcitabine resistance via MEK/ERK pathway and is modulated by circRPS29/miR-770–5p axis in PDAC

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY Drug Resistance Updates Pub Date : 2024-03-12 DOI:10.1016/j.drup.2024.101079
Wenjie Huang , Xiaojun Hu , Xiang He , Dongyue Pan , Zhaorong Huang , Zhanfeng Gu , Guobing Huang , Ping Wang , Chunhui Cui , Yingfang Fan
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Abstract

Aims

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.

Methods

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.

Results

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.

Conclusion

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.

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TRIM29 在 PDAC 中通过 MEK/ERK 通路促进吉西他滨耐药,并受 circRPS29/miR-770-5p 轴的调节
胰腺导管腺癌(PDAC)是一种致死率极高的疾病。以吉西他滨(GEM)为基础的化疗仍是晚期胰腺导管腺癌患者的一线药物。然而,吉西他滨耐药会影响其疗效。因此,迫切需要找到有效的治疗靶点来克服吉西他滨耐药性。通过探索GEO和TCGA数据集,确定了含三方基元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了调控轴,并通过力学实验进行了验证。然后,通过体外和体内实验验证了 TRIM29 在 PDAC GEM 抗性中的作用。TRIM29的高表达与PDAC的不良预后有关,功能实验证明TRIM29促进了PDAC-GR细胞的GEM抵抗(GR)。此外,我们还发现,circRPS29通过与miR-770-5p的竞争性相互作用促进了TRIM29的表达,进而激活了MEK/ERK信号通路。此外,体外和体内功能实验都证明,circRPS29/miR-770-5p/TRIM29轴通过激活MEK/ERK信号通路促进了PDAC GEM的耐药性。我们的研究结果明确了circRPS29/miR-770-5p/TRIM29-MEK/ERK信号轴在PDAC GEM耐药中的重要作用,为PDAC治疗提供了新的治疗靶点。
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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
期刊介绍: Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research
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