OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma.
OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma.
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OXCT1 通过 NF-κB 通路增强胰管腺癌中的吉西他滨耐药性
DOI：
10.3389/fonc.2021.698302
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发表时间：
2021
影响因子：
4.7
通讯作者：
Gao C
中科院分区：
文献类型：
--
作者：
Ding J;Li H;Liu Y;Xie Y;Yu J;Sun H;Xiao D;Zhou Y;Bao L;Wang H;Gao C
背景胰腺导管腺癌（PDAC）是一种5年生存率低于10%的恶性肿瘤。吉西他滨（GEM）是PDAC化疗最常用的药物。然而，绝大多数PDAC患者在GEM治疗后产生耐药性。方法通过生物信息学分析筛选GEM耐药基因。我们使用免疫组织化学分析3-氧代酸CoA-转移酶1（OXCT 1）在PDAC组织中的表达。生存数据采用Kaplan-Meier曲线进行分析。采用真实的-时间定量PCR和蛋白质印迹分析定量OXCT 1和NF-κB信号通路相关基因的表达水平。流式细胞仪检测细胞凋亡率。进行集落形成测定以测量细胞增殖水平。使用RTCA进行细胞的细胞毒性测定。通过基因集富集分析鉴定OXCT 1的下游途径。还在小鼠模型中测定了体内对GEM的肿瘤生长反应。结果生物信息学分析表明OXCT 1基因是导致GEM耐药的关键基因。高OXCT 1表达的患者在GEM治疗下表现出较短的无复发生存期。OXCT 1在PDAC细胞系中的过表达对GEM处理后的凋亡具有抑制作用。然而，OXCT 1的下调表现出相反的效果。阻断NF-κB信号通路也能降低PDAC细胞对GEM的抵抗。GEM在体内诱导的肿瘤生长抑制在OXCT 1过表达后减少。此外，OXCT 1对PDAC细胞系中GEM不应性的作用通过使用NF-κB抑制剂逆转。结论OXCT 1在体内外均通过NF-κB信号通路促进PDAC对GEM的耐药性。我们的研究结果表明，OXCT 1可作为PDAC患者的潜在治疗靶点。
Background Pancreatic ductal adenocarcinoma (PDAC) is a type of malignant tumor with a five-year survival rate of less than 10%. Gemcitabine (GEM) is the most commonly used drug for PDAC chemotherapy. However, a vast majority of patients with PDAC develop resistance after GEM treatment. Methods We screened for GEM resistance genes through bioinformatics analysis. We used immunohistochemistry to analyze 3-oxoacid CoA-transferase 1 (OXCT1) expression in PDAC tissues. The survival data were analyzed using the Kaplan–Meier curve. The expression levels of the genes related to OXCT1 and the NF-κB signaling pathway were quantified using real−time quantitative PCR and western blot analyses. We performed flow cytometry to detect the apoptosis rate. Colony formation assay was performed to measure the cell proliferation levels. The cytotoxicity assays of cells were conducted using RTCA. The downstream pathway of OXCT1 was identified via the Gene Set Enrichment Analysis. Tumor growth response to GEM in vivo was also determined in mouse models. Results Bioinformatics analysis revealed that OXCT1 is the key gene leading to GEM resistance. Patients with high OXCT1 expression exhibited short relapse-free survival under GEM treatment. OXCT1 overexpression in PDAC cell lines exerted inhibitory effect on apoptosis after GEM treatment. However, the down-regulation of OXCT1 showed the opposite effect. Blocking the NF-κB signaling pathway also reduced GEM resistance of PDAC cells. Tumor growth inhibition induced by GEM in vivo reduced after OXCT1 overexpression. Moreover, the effect of OXCT1 on GEM refractoriness in PDAC cell lines was reversed through using an NF-κB inhibitor. Conclusion OXCT1 promoted GEM resistance in PDAC via the NF-κB signaling pathway both in vivo and in vitro. Our results suggest that OXCT1 could be used as a potential therapeutic target for patients with PDAC.
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影响因子：
4.3
作者：
Martinez-Outschoorn, Ubaldo E.;Lin, Zhao;Sotgia, Federica
通讯作者：
Sotgia, Federica
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