Journal Article Research Support, Non-U.S. Gov't Ppublish 34 citations
PubMed: 31999643 DOI: 10.1172/JCI131919
Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer.
J Clin Invest 130(5):2509-2526
Authors: Peter Dietrich, Laura Wormser, Valerie Fritz, Tatjana Seitz, Monica De Maria, Alexandra Schambony, Andreas E Kremer, Claudia Günther, Timo Itzel, Wolfgang E Thasler, Andreas Teufel, Jonel Trebicka, Arndt Hartmann, Markus F Neurath, Stephan von Hörsten, Anja K Bosserhoff, Claus Hellerbrand
Affiliations
- Institute of Biochemistry, Emil-Fischer-Zentrum.
- Department of Medicine 1, University Hospital Erlangen, and.
- Biology Department, Developmental Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
- Department of Internal Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Hepacult GmbH, Planegg, Germany.
- Department of Medicine I, University Hospital Bonn, Bonn, Germany.
- Institute of Pathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
- Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg, Erlangen, Germany.
- Department of Experimental Therapy, Franz Penzoldt Center, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
Abstract
Hepatocellular carcinoma (HCC) is clearly age-related and represents one of the deadliest cancer types worldwide. As a result of globally increasing risk factors including metabolic disorders, the incidence rates of HCC are still rising. However, the molecular hallmarks of HCC remain poorly understood. Neuropeptide Y (NPY) and NPY receptors represent a highly conserved, stress-activated system involved in diverse cancer-related hallmarks including aging and metabolic alterations, but its impact on liver cancer had been unclear. Here, we observed increased expression of NPY5 receptor (Y5R) in HCC, which correlated with tumor growth and survival. Furthermore, we found that its ligand NPY was secreted by peritumorous hepatocytes. Hepatocyte-derived NPY promoted HCC progression by Y5R activation. TGF-β1 was identified as a regulator of NPY in hepatocytes and induced Y5R in invasive cancer cells. Moreover, NPY conversion by dipeptidylpeptidase 4 (DPP4) augmented Y5R activation and function in liver cancer. The TGF-β/NPY/Y5R axis and DPP4 represent attractive therapeutic targets for controlling liver cancer progression.
MeSH
Hepatocytes, Neoplasms, Liver, Liver Neoplasms, Neuropeptides, Neuropeptide Y
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