Hung Yu-Hsuan, Hou Ya-Chin, Hsu Shih-Han, Wang Li-Yun, Tsai Ya-Li, Shan Yan-Shen, Su Yung-Yeh, Hung Wen-Chun, Chen Li-Tzong
National Institute of Cancer Research, National Health Research Institutes Tainan 704, Taiwan.
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University Tainan 704, Taiwan.
Am J Cancer Res. 2023 Aug 15;13(8):3417-3432. eCollection 2023.
Perineural invasion and neurogenesis are frequently observed in pancreatic ductal adenocarcinoma (PDAC), and they are associated with a poor prognosis. Axon guidance factor semaphorin 3A (SEMA3A) is upregulated in PDAC. However, it remains unclear whether cancer-derived SEMA3A influences nerve innervation and pancreatic tumorigenesis. analyses were performed using PROGgene and NetworkAnalyst to clarify the importance of SEMA3A and its receptors, plexin A1 (PLXNA1) and neuropilin 2 (NRP2), in pancreatic cancer. assays, including migration, neurite outgrowth, and 3D recruitment, were performed to study the effects of SEMA3A on neuronal behaviors. Additionally, an orthotopic animal study using C57BL/6 mice was performed to validate the findings. Expression of SEMA3A and its receptors predicted worse prognosis for PDAC. Cancer-derived SEMA3A promoted neural migration, neurite outgrowth, and neural recruitment. Furthermore, SEMA3A-induced effects depended on PLXNA1, NRP2, and MAPK activation. Trametinib, an approved MAPK kinase (MEK) inhibitor, counteracted SEMA3A-enhanced neuronal activity . Inhibition of SEMA3A by shRNA in pancreatic cancer cells resulted in decreased neural recruitment, tumor growth, and dissemination . Our results suggested that cancer-secreted SEMA3A plays an important role in promoting neo-neurogenesis and progression of PDAC.
在胰腺导管腺癌（PDAC）中经常观察到神经周围浸润和神经发生，并且它们与预后不良相关。轴突导向因子信号素3A（SEMA3A）在PDAC中上调。然而，癌症来源的SEMA3A是否影响神经支配和胰腺肿瘤发生仍不清楚。使用PROGgene和NetworkAnalyst进行分析，以阐明SEMA3A及其受体丛状蛋白A1（PLXNA1）和神经纤毛蛋白2（NRP2）在胰腺癌中的重要性。进行了包括迁移、神经突生长和三维募集等实验，以研究SEMA3A对神经元行为的影响。此外，使用C57BL/6小鼠进行了原位动物研究，以验证这些发现。SEMA3A及其受体的表达预示着PDAC的预后较差。癌症来源的SEMA3A促进神经迁移、神经突生长和神经募集。此外，SEMA3A诱导的效应依赖于PLXNA1、NRP2和丝裂原活化蛋白激酶（MAPK）的激活。曲美替尼是一种已获批准的MAPK激酶（MEK）抑制剂，可抵消SEMA3A增强的神经元活性。在胰腺癌细胞中通过短发夹RNA（shRNA）抑制SEMA3A导致神经募集、肿瘤生长和扩散减少。我们的结果表明，癌症分泌的SEMA3A在促进PDAC的新神经发生和进展中起重要作用。
