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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 Article has an altmetric score of 19

Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer

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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 1

Upregulation of NPY5 receptor in HCC.

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Upregulation of NPY5 receptor in HCC.
(A) Explanted, tumor-bearing liver...
(A) Explanted, tumor-bearing liver (representative image) derived from an aged C3H/HeN mouse, and bar graph (below) depicting percentages of tumor-bearing mice, age 18 months (n = 12). (B) Representative H&E staining (20-fold original magnification; n = 12) depicting histological heterogeneity of HCC derived from aged C3H mice. (C) Normalized mRNA levels of NPY, Y1R, Y2R, and Y5R in nontumorous livers comparing young (n = 11) with aged (n = 22) mice. (D) Representative images (10-fold original magnification; H&E and Y5R staining) and IHC analysis of Y5R levels in nontumorous livers comparing young (n = 6) and aged (n = 6) mice. (E) Normalized NPY, Y1R, Y2R, and Y5R mRNA levels in HCC compared with corresponding nontumorous liver tissues derived from aged C3H mice (n = 8) (box-and-whisker plots [minimum to maximum]; “+” indicates mean values). (F) Representative images (H&E and Y5R staining; 20-fold original magnification) of age-related HCC and peritumorous tissues derived from C3H mice (n = 12). (G) Representative images (H&E and Y5R staining; 40-fold original magnification); Y5R protein expression (IHC) in nontumorous liver tissues of younger (<65 years) (n = 57) compared with older (>65 years) (n = 51) HCC patients. (H) Y5R mRNA levels in paired HCC and corresponding peritumorous tissues (n = 31 pairs). (I) Representative images (H&E and Y5R staining; 40-fold original magnification) and IHC analysis of Y5R protein levels in HCC compared with corresponding peritumorous tissues (n = 231). Data are presented as mean ± SEM. Statistical significance was determined by 2-tailed, unpaired t test (C and D), 2-tailed, paired t test (E and H), 2-sided Fisher’s exact test and Spearman’s correlation (G and I), and uni- and multivariate analysis (ordinal regression analysis, link function: logit) (G). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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