CD74 promotes perineural invasion of cancer cells and mediates neuroplasticity via the AKT/EGR-1/GDNF axis in pancreatic ductal adenocarcinoma.

Abstract

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. 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. 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. 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.

• Authors: Jun-Feng Zhang, Ling-Ye Tao, Min-Wei Yang, Da-Peng Xu, Shu-Heng Jiang, Xue-Liang Fu, De-Jun Liu, Yan-Miao Huo, Wei Liu, Jian-Yu Yang, Rong Hua, Ping Lu, Yong-Wei Sun
• Journal: Cancer letters (Cancer Lett) Vol. 508 Pg. 47-58 (06 28 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 33766751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier B.V.

Chemical References

• Antigens, CD
• EGR1 protein, human
• Early Growth Response Protein 1
• GDNF protein, human
• Glial Cell Line-Derived Neurotrophic Factor
• Sialyltransferases
• ST6GAL1 protein, human
• Proto-Oncogene Proteins c-akt

Topics

• Antigens, CD (metabolism)
• Carcinoma, Pancreatic Ductal (metabolism, pathology)
• Early Growth Response Protein 1 (metabolism)
• Glial Cell Line-Derived Neurotrophic Factor (metabolism)
• Humans
• Neoplasm Invasiveness
• Neuronal Plasticity
• Neurons (metabolism, pathology)
• Pancreatic Neoplasms (metabolism, pathology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Sialyltransferases (metabolism)
• Signal Transduction
• Tumor Microenvironment
• Up-Regulation