Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Centre for Pancreatic Diseases of Xi'an Jiaotong University, Xi'an, China.
Cell Death Dis. 2022 Apr 21;13(4):387. doi: 10.1038/s41419-022-04799-5.
Perineural invasion (PNI) is a pathologic feature of pancreatic cancer and is associated with poor outcomes, metastasis, and recurrence in pancreatic cancer patients. However, the molecular mechanism of PNI remains unclear. The present study aimed to investigate the mechanism that HGF/c-Met pathway facilitates the PNI of pancreatic cancer. In this study, we confirmed that c-Met expression was correlated with PNI in pancreatic cancer tissues. Activating the HGF/c-Met signaling pathway potentiated the expression of nerve growth factor (NGF) to recruit nerves and promote the PNI. Activating the HGF/c-Met signaling pathway also enhanced the migration and invasion ability of cancer cells to facilitate cancer cells invading nerves. Mechanistically, HGF/c-Met signaling pathway can active the mTOR/NGF axis to promote the PNI of pancreatic cancer. Additionally, we found that knocking down c-Met expression inhibited cancer cell migration along the nerve, reduced the damage of the sciatic nerve caused by cancer cells and protected the function of the sciatic nerve in vivo. Taken together, our findings suggest a supportive mechanism of the HGF/c-Met signaling pathway in promoting PNI by activating the mTOR/NGF axis in pancreatic cancer. Blocking the HGF/c-Met signaling pathway may be an effective target for the treatment of PNI.
神经周围侵犯（PNI）是胰腺癌的一种病理特征，与胰腺癌患者的不良预后、转移和复发有关。然而，PNI 的分子机制尚不清楚。本研究旨在探讨 HGF/c-Met 通路促进胰腺癌 PNI 的机制。在这项研究中，我们证实 c-Met 表达与胰腺癌组织中的 PNI 相关。激活 HGF/c-Met 信号通路增强了神经生长因子（NGF）的表达，以招募神经并促进 PNI。激活 HGF/c-Met 信号通路还增强了癌细胞的迁移和侵袭能力，促进了癌细胞侵犯神经。在机制上，HGF/c-Met 信号通路可以激活 mTOR/NGF 轴，促进胰腺癌的 PNI。此外，我们发现敲低 c-Met 表达可抑制癌细胞沿神经的迁移，减少癌细胞对坐骨神经造成的损伤，并在体内保护坐骨神经的功能。总之，我们的研究结果表明，HGF/c-Met 信号通路通过激活 mTOR/NGF 轴在促进胰腺癌 PNI 中起支持作用。阻断 HGF/c-Met 信号通路可能是治疗 PNI 的有效靶点。
