Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer
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
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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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 8

Hepatocyte-derived NPY mediates chemotaxis via activation of Y5R.

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Hepatocyte-derived NPY mediates chemotaxis via activation of Y5R. (A) Ca...
(A) Cartoon hypothesis that an NPY gradient (downregulation of NPY in HCC cells and NPY expression by peritumorous hepatocytes) impacts chemotaxis of HCC cells via Y5R activation. (B–G) Real-time cell migration (B) and Boyden chamber (C–G) analysis (upper chamber [UC] and lower chamber [LC]) of chemotaxis of HCC cells toward recombinant NPY (B [n = 6] and C [n = 8]), Y5R agonist BWX46 (Y5R-Ago) (n = 3) (D), and NPY with or without Y5R inhibition by CGP71683 (Y5R-Inh) (n = 3) (E) or by NPY-mediated and/or siRNA pool–mediated Y5R knockdown (n = 3; box-and-whisker plots [min to max]) (F). (G) NPY or supernatants of primary human hepatocytes (PHH) with or without Y5R-Inh or an NPY-neutralizing antibody (anti-NPY Ab) (n = 3; box-and-whisker plots [min to max]). (H) Representative IHC (H&E, Y5R, cyclin D1, p-AKT, p-ERK) and coimmunofluorescence (Y5R and NPY) analysis (serial sections) of HCC and peritumorous tissue applying the orthotopic murine HCC model (20-fold original magnification; n = 6). Arrowheads: tumor-parenchyma edge. (I and J) cAMP signaling (analyzed by bioluminescence resonance energy transfer technique) of PLC cells treated with NPY and/or Y5R-Inh (I) or different doses of Y5R-Ago (box-and-whisker plots [min to max]; n = 3) (J). (K) Boyden chamber analysis of migration of HCC cells toward NPY or BWX46 with or without cotreatment with the cAMP inducer forskolin (Forsk.) (n = 4; box-and-whisker plots [min to max]). (L) Boyden chamber analysis of invasion of HCC cells toward NPY in the lower compartment (n = 4; box-and-whisker plots [min to max]). Data are presented as mean ± SEM. Statistical significance was determined by ordinary 1-way ANOVA and Dunnett’s multiple-comparisons test (B–G and I–L). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.