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.
View: Text | PDF
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

×

Figure 9

Y5R expression in HCC cells at sites of stromal invasion and TGF-β–mediated effects on Y5R expression in HCC cells.

Options: View larger image (or click on image) Download as PowerPoint
Y5R expression in HCC cells at sites of stromal invasion and TGF-β–media...
(A) Representative images of Y5R (and H&E) immunostaining (10- and 40-fold original magnification, respectively) of human HCC tissues at sites of stromal infiltration (n = 122). (B) Y5R mRNA expression levels (qRT-PCR analysis) in HCC cells (PLC) treated with different doses of recombinant TGF-β (n = 3). (C and D) mRNA expression levels (qRT-PCR analysis) of epithelial-mesenchymal transition (EMT) markers (vimentin, S100A4, SNAIL, and N-cadherin) (C) and Y5R (D) in HCC cells (PLC) after 96 hours of treatment with recombinant TGF-β with or without cotreatment with the specific TGF-β receptor 1 (TGFBR1) inhibitor galunisertib (10 μM) (n = 3). (E) Western blot analysis (representative images, n = 3) of Y5R protein levels in HCC cells after treatment with different doses of TGF-β (96 hours), with or without cotreatment with galunisertib (10 μM). (F) Paired Y5R and TGF-β mRNA expression analysis (qRT-PCR analysis, relative to β-actin) in HCC patient tissues (n = 64). (G) Real-time cell migration (xCELLigence) analysis of HCC cells (PLC) treated with low-dose recombinant NPY (10 nM) to induce nondirected migration (i.e., chemokinesis) (n = 6). (H) Boyden chamber analysis of chemokinesis of HCC cells (PLC) treated or not treated with recombinant TGF-β (5 ng/mL) and/or the specific Y5R inhibitor CGP71683 (Y5R-Inh) (n = 3). Data are presented as mean ± SEM. Statistical significance was determined by ordinary 1-way ANOVA together with Dunnett’s multiple-comparisons test (B–D and H), 2-tailed, unpaired t test (G), or Pearson correlation (F). *P < 0.05, **P < 0.01, ***P < 0.001.