A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2.
A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2.
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DOI：
10.1158/0008-5472.can-15-2841
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发表时间：
2016-07-01
期刊：
影响因子：
11.2
通讯作者：
Hussain SP
中科院分区：
文献类型：
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作者：
Yang S;He P;Wang J;Schetter A;Tang W;Funamizu N;Yanaga K;Uwagawa T;Satoskar AR;Gaedcke J;Bernhardt M;Ghadimi BM;Gaida MM;Bergmann F;Werner J;Ried T;Hanna N;Alexander HR;Hussain SP
巨噬细胞移动抑制因子（MIF）异常表达的胰腺癌特别具有侵袭性。为了确定在具有高MIF表达的肿瘤中驱动疾病侵袭性的关键信号传导途径，我们分析了多个胰腺导管腺癌（PDAC）患者队列中高和低MIF表达肿瘤中编码和非编码基因的表达。确定的关键基因和途径与患者生存有关，并使用细胞系、基因工程小鼠模型和PDAC患者队列进行了机械、功能和临床表征。在这里，我们报告了一种新的MIF驱动的信号通路的证据，抑制孤儿核受体NR 3C 2，以前未描述的肿瘤抑制剂，影响PDAC的侵略性和生存。在机制上，MIF上调靶向NR 3C 2的miR-301 b并抑制其表达。表达高水平MIF的PDAC肿瘤显示miR-301 b水平升高和NR 3C 2水平降低。此外，NR 3C 2表达水平的降低与PDAC患者的多个独立队列中较差的生存率相关。功能分析表明，NR 3C 2抑制上皮细胞向间充质细胞的转化，并增强对吉西他滨（一种用于PDAC标准治疗的化疗药物）的敏感性。此外，在PDAC的基因工程小鼠模型中，MIF的基因缺失破坏了MIF-mir-301 b-NR 3C 2信号传导轴，减少了转移并延长了生存期。总之，我们的结果为候选疗法提供了临床前原理验证，以靶向新描述的MIF-miR-301 b-NR 3C 2信号传导轴用于PDAC管理。
Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and non-coding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients. The key genes and pathways identified were linked to patient survival and were mechanistically, functionally and clinically characterized using cell lines, a genetically engineered mouse model and PDAC patient cohorts. Here we report evidence of a novel MIF-driven signaling pathway that inhibits the orphan nuclear receptor NR3C2, a previously undescribed tumor suppressor that impacts aggressiveness and survival in PDAC. Mechanistically, MIF upregulated miR-301b which targeted NR3C2 and suppressed its expression. PDAC tumors expressing high levels of MIF displayed elevated levels of miR-301b and reduced levels of NR3C2. Additionally, reduced levels of NR3C2 expression correlated with poorer survival in multiple independent cohorts of PDAC patients. Functional analysis showed that NR3C2 inhibited epithelial-to-mesenchymal transition and enhanced sensitivity to the gemcitabine, a chemotherapeutic drug used in PDAC standard of care. Furthermore, genetic deletion of MIF disrupted a MIF-mir-301b-NR3C2 signaling axis, reducing metastasis and prolonging survival in a genetically engineered mouse model of PDAC. Taken together, our results offer a preclinical proof-of-principle for candidate therapies to target a newly described MIF-miR-301b-NR3C2 signaling axis for PDAC management.