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 6

Peritumorous NPY expression by hepatocytes correlates with hepatic fibrosis.

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Peritumorous NPY expression by hepatocytes correlates with hepatic fibro...
(A and B) Immunohistochemical/immunofluorescence analysis of NPY staining (representative images, 40-fold original magnification in A, 20-fold original magnification in B) of peritumorous liver tissues applying a tissue microarray (TMA) (n = 231). (C) Paired NPY and collagen type I (Coll1a) mRNA expression, by quantitative reverse transcriptase PCR (qRT-PCR) analysis, in human peritumorous liver tissues (n = 24). (D) IHC analysis (representative images [10- and 40-fold original magnification, respectively] and quantification) of fibrosis (applying the Desmet score system) in peritumorous liver tissues with high (n = 64) as compared with low (n = 33) NPY expression levels applying a human tissue microarray. (E) IHC analysis (representative images and quantification) of α-smooth muscle actin (α-SMA) expression in peritumorous liver tissues with high (n = 58) as compared with low (n = 33) NPY expression levels applying a human TMA; the representative images (40-fold original magnification) display the same loci derived from paired (i.e., serial) tissue sections from 1 patient. Data are presented as mean ± SEM. Statistical significance was determined by Pearson correlation (C) or by 2-sided Fisher’s exact test together with Spearman’s correlation analysis (D and E). ****P < 0.0001.