Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer
Peter Dietrich, … , Anja K. Bosserhoff, Claus Hellerbrand
Peter Dietrich, … , Anja K. Bosserhoff, Claus Hellerbrand
Published January 30, 2020
Citation Information: J Clin Invest. 2020;130(5):2509-2526. https://doi.org/10.1172/JCI131919.
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Research Article Aging Hepatology

Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer

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.

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

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Figure 4

NPY is secreted by peritumorous hepatocytes and correlates with survival and Y5R expression in HCC.

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NPY is secreted by peritumorous hepatocytes and correlates with survival...
(A and B) Immunohistochemical/immunofluorescence analysis of NPY expression in paired nontumorous (Peri-HCC) and HCC tissues of patients (representative images [20-fold original magnification] and quantification) applying a tissue microarray (n = 231) (A) and representative images (40-fold original magnification) displaying primary human hepatocytes (PHH) and HCC cells (Hep3B) (n = 3) (B). (C) ELISA analysis of NPY expression in protein lysates and in cell culture supernatants of PHHs (n = 4) and HCC cells (PLC [n = 3], Hep3B [n = 3], HepG2 [n = 3]) (data are shown as box-and-whisker plots [min to max]). (D and E) Coimmunofluorescence staining of NPY and Y5R protein in in vitro cocultures of hepatocytes and HCC cells (n = 2) (40-fold original magnification) (D) and the murine orthotopic HCC model (n = 6) (20-fold original magnification) (E). (F) Comparison of survival of HCC patients with high (n = 31) and low (n = 27) NPY immunoreactivity in peritumorous liver tissue applying a tissue microarray. (G) Representative images (40-fold original magnification) and IHC analysis of NPY and Y5R staining of paired peritumorous liver tissues and corresponding HCC tissues applying a human tissue microarray (n = 103). Data are presented as mean ± SEM. Statistical significance was determined by 2-sided Fisher’s exact test together with Spearman’s correlation analysis (A, F, and G) and uni- and multivariate analysis applying ordinal regression analysis (link function: logit) (F). *P < 0.05, **P < 0.01, ****P < 0.0001.