HIF-1α mediates tumor-nerve interactions through the up-regulation of GM-CSF in pancreatic ductal adenocarcinoma (Retracted article. See vol. 558, 2023)
HIF-1α mediates tumor-nerve interactions through the up-regulation of GM-CSF in pancreatic ductal adenocarcinoma (Retracted article. See vol. 558, 2023)
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HIF-1 α 通过上调胰腺导管腺癌中 GM-CSF 介导肿瘤与神经的相互作用
DOI：
10.1016/j.canlet.2019.03.036
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Hao, Jihui
中科院分区：
文献类型：
--
作者：
Wang, Haotian;Jia, Rujiang;Hao, Jihui
神经周围侵犯（PNI）是胰腺导管腺癌（PDAC）的典型病理特征。 PNI与PDAC患者的不良预后相关，然而，PNI发生的潜在分子机制尚未完全揭示。在这项研究中，我们发现 PDAC 细胞中 GM-CSF 和 HIF-1 α 的表达显着增加。 HIF-1α和GM-CSF的过度表达与PNI和癌症相关疼痛的发生率增加以及PDAC患者的总生存期缩短密切相关。 PDAC 细胞中 GM-CSF 的表达由 HIF-1 α 通过直接结合 GM-CSF 启动子中的缺氧反应元件介导。激活的HIF-1α可以上调GM-CSF的表达和分泌，促进雪旺细胞在肿瘤微环境中的迁移。此外，GM-CSF 过表达可以通过 HIF-1 α 敲低来挽救雪旺细胞迁移的抑制。此外，在 PDAC 异种移植小鼠模型中，使用 PX478 抑制 HIF-1 α 可显着降低 GM-CSF 的表达水平并降低 PNI。总体而言，我们的结果表明 HIF-1 α/GM-CSF 通路参与肿瘤-神经相互作用并促进 PNI 的发生。阻断该信号可能有助于抑制 PDAC 进展。
Perineural invasion (PNI) is a typical pathological feature of pancreatic ductal adenocarcinoma (PDAC). PNI is associated with poor prognosis of PDAC patients, however, the underlying molecular mechanisms in the development of PNI have not been fully revealed. In this study, we found that the expression of GM-CSF and HIF-1 alpha were dramatically increased in PDAC cells. The overexpression of HIF-1 alpha and GM-CSF closely correlated with increased occurrence of PNI and cancer-related pain and shortened overall survival in PDAC patients. GM-CSF expression in PDAC cells was mediated by HIF-1 alpha through direct binding to the hypoxia response element in the GM-CSF promoter. The activated HIF-1 alpha can up-regulate GM-CSF expression and secretion, which promoted the migration of Schwann cells in tumor microenvironment. Furthermore, GM-CSF overexpression could rescue the inhibition of Schwann cells migration by HIF-1 alpha knockdown. Moreover, HIF-1 alpha inhibition with PX478 drastically reduced the expression level of GM-CSF and decreased the PNI in a PDAC xenograft mouse model. Overall, our results demonstrated that the HIF-1 alpha/GM-CSF pathway is involved in the tumor-nerve interactions and promotes the occurrence of PNI. The blockade of this signal might help to inhibit PDAC progression.