CD74 Promotes Perineural Invasion of Cancer Cells and Mediates Neuroplasticity Via the AKT/EGR-1/GDNF Axis in Pancreatic Ductal Adenocarcinoma

Abstract

Background: Perineural invasion (PNI) is a common feature of pancreatic ductal adenocarcinoma (PDAC) and is one of the important causes of local recurrence in resected pancreatic cancer, but the molecular mechanism remains largely unexplored. Methods: Here, we used immunohistochemistry staining to determine the expression of CD74. Then the in vivo PNI model, in vitro neuroplasticity assay, cell proliferation assay, wound healing and Transwell-based invasion assay were performed to examine the function of CD74 in pancreatic cancer cell lines. ChIP assay and Luciferase reporter assay were used to illustrate the mechanism underlying CD74 induced GDNF expression. Findings: We confirmed that the expression level of CD74 was an independent predictor of PNI and poor prognosis for PDAC. Moreover, we found that upregulation of CD74 on PDAC enhanced its migration and invasive capabilities and potentiated the secretion of neurotrophic factor GDNF to promote the neuroplasticity. Mechanistically, CD74 promoted GDNF production via the AKT/EGR-1/GDNF axis in PDAC. Interpretation: Taken together, our findings suggest a supportive role of CD74 in the PNI of PDAC, and deepen our understanding of how cancer cells promote neuroplasticity in the microenvironment of PDAC. Funding: This work was supported by grants from National Natural Science Foundation of China No.81401931 (Jun-Feng Zhang), 81602414(Jian-Yu Yang), 81702739 (Xue-Liang Fu), 81802317(Min-Wei Yang), and additional grants from Science and Technology funds of School of Medicine, Shanghai Jiao Tong University No. 14XJ10022 (Jun-Feng Zhang), Scientific research project of Shanghai municipal health and Family Planning Commission No. 201740218 (Jun-Feng Zhang). Conflict of Interest: The authors have no conflicts of interest to declare. Ethical Approval: All the patients provided written informed consent before admission, and the study was approved by the Research Ethics Committee of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University.