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Pancreatic ductal adenocarcinoma cells regulated the gemcitabine-resistance function of CAFs by LINC00460
Cancer Science ( IF 5.7 ) Pub Date : 2022-09-01 , DOI: 10.1111/cas.15547 Xiao-Xu Zhu 1 , Jian-Hui Li 1 , Xuhao Ni 1 , Xiao Wu 1 , Xun Hou 2 , Ya-Xiong Li 1 , Shi-Jin Li 1 , Wei Zhao 3 , Xiao-Yu Yin 1
Cancer Science ( IF 5.7 ) Pub Date : 2022-09-01 , DOI: 10.1111/cas.15547 Xiao-Xu Zhu 1 , Jian-Hui Li 1 , Xuhao Ni 1 , Xiao Wu 1 , Xun Hou 2 , Ya-Xiong Li 1 , Shi-Jin Li 1 , Wei Zhao 3 , Xiao-Yu Yin 1
Affiliation
Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal malignancy with extremely poor prognosis. Gemcitabine resistance is a major challenge in the treatment of PDAC. Here, we showed that LINC00460 was associated with the response to gemcitabine both in PDAC patients and PDAC-PDX. After knocking down LINC00460 in PDAC tumor cells, results of RNA sequencing followed by gene ontology analysis indicated that LINC00460 influenced the activity of growth factors and modified the extracellular matrix. FISH showed that LINC00460 is mostly located in the cytoplasm. Results of RNA pull-down, LC–MS/MS, RIP, and immunoblotting confirmed that LINC00460 could directly bind to PDAP1. Furthermore, we demonstrated that LINC00460 mediated the cellular communication of PDAC tumor cells and CAFs by PDAP1/PDGFA/PDGFR signaling pathway and regulated the gemcitabine-resistance function of CAFs, which could be reversed by treatment with a PDGFR inhibitor (crenolanib). PDAC-PDX tumors with lower expression of LINC00460 showed a better response to gemcitabine plus crenolanib treatment. Our finding supported the application of LINC00460 in precision medicine that uses gemcitabine plus crenolanib to treat PDAC with low expression of LINC00460.
中文翻译:
胰腺导管腺癌细胞通过 LINC00460 调节 CAF 的吉西他滨耐药功能
胰腺导管腺癌(PDAC)是一种高度致命的恶性肿瘤,预后极差。吉西他滨耐药是治疗 PDAC 的主要挑战。在这里,我们发现 LINC00460 与 PDAC 患者和 PDAC-PDX 对吉西他滨的反应有关。在 PDAC 肿瘤细胞中敲除 LINC00460 后,RNA 测序结果和基因本体分析表明 LINC00460 影响生长因子的活性并修饰细胞外基质。FISH显示LINC00460主要位于细胞质中。RNA pull-down、LC-MS/MS、RIP 和免疫印迹结果证实 LINC00460 可以直接与 PDAP1 结合。此外,我们证明 LINC00460 通过 PDAP1/PDGFA/PDGFR 信号通路介导 PDAC 肿瘤细胞和 CAF 的细胞通讯,并调节 CAF 的吉西他滨抗性功能,这可以通过用 PDGFR 抑制剂 (crenolanib) 治疗来逆转。LINC00460 表达较低的 PDAC-PDX 肿瘤对吉西他滨加 crenolanib 治疗表现出更好的反应。我们的发现支持 LINC00460 在精准医学中的应用,即使用吉西他滨加 crenolanib 治疗 LINC00460 低表达的 PDAC。
更新日期:2022-09-01
中文翻译:
胰腺导管腺癌细胞通过 LINC00460 调节 CAF 的吉西他滨耐药功能
胰腺导管腺癌(PDAC)是一种高度致命的恶性肿瘤,预后极差。吉西他滨耐药是治疗 PDAC 的主要挑战。在这里,我们发现 LINC00460 与 PDAC 患者和 PDAC-PDX 对吉西他滨的反应有关。在 PDAC 肿瘤细胞中敲除 LINC00460 后,RNA 测序结果和基因本体分析表明 LINC00460 影响生长因子的活性并修饰细胞外基质。FISH显示LINC00460主要位于细胞质中。RNA pull-down、LC-MS/MS、RIP 和免疫印迹结果证实 LINC00460 可以直接与 PDAP1 结合。此外,我们证明 LINC00460 通过 PDAP1/PDGFA/PDGFR 信号通路介导 PDAC 肿瘤细胞和 CAF 的细胞通讯,并调节 CAF 的吉西他滨抗性功能,这可以通过用 PDGFR 抑制剂 (crenolanib) 治疗来逆转。LINC00460 表达较低的 PDAC-PDX 肿瘤对吉西他滨加 crenolanib 治疗表现出更好的反应。我们的发现支持 LINC00460 在精准医学中的应用,即使用吉西他滨加 crenolanib 治疗 LINC00460 低表达的 PDAC。