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 2

Y5R enhances tumorigenicity of HCC and correlates with poor survival.

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Y5R enhances tumorigenicity of HCC and correlates with poor survival. (A...
(A) Y5R mRNA levels in primary human hepatocytes (PHH) (n = 5) compared with human HCC cells Hep3B (n = 3), HepG2 (n = 3), Huh-7 (n = 4), and PLC (n = 3). (B) Y5R Western blot analysis: representative image (PHHs from 2 donors [d#1, d#2]) and quantification of protein levels (PHHs [n = 4] compared with Hep3B [n = 3], HepG2 [n = 3], Huh-7 [n = 3], PLC [n = 5]). (C and D) HCC cells transfected with siRNA pools against Y5R (si-Y5R) or a control siRNA pool (Control). (C) Coimmunofluorescence (Y5R, Ki-67) images (20-fold original magnification; n = 2). (D) Representative proliferation curves and quantification (n = 3) (box-and-whisker plots [min to max]). (E) Correlated Y5R and cyclin D1 mRNA (human HCC tissues; n = 17). (F) Clonogenicity (colony numbers, sizes, representative images) of PLC cells after RNAi-mediated Y5R knockdown (n = 3). (G) SurvExpress analysis of Y5R expression and overall survival (TCGA data; n = 381). Computational stratification (low-risk and high-risk groups) based on prognostic index. (H and I) Comparison of survival of patients with low (n = 17) and high (n = 39) Y5R expression (H) and tumor stages of patients with low (n = 25) and high (n = 92) Y5R expression (I) based on IHC analysis of HCC tissue microarray samples. Data are presented as mean ± SEM. Statistical significance was determined by ordinary 1-way ANOVA and Dunnett’s multiple-comparisons test (A and B); 2-tailed, unpaired t test (D and F); Pearson correlation (E); 2-sided Fisher’s exact test, Spearman’s correlation, and uni- and multivariate analysis (ordinal regression analysis, link function: logit) (H and I); and log-rank testing and hazard ratio estimates (G). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.