Pancreatic polypeptide interacts with neuropeptide Y4 receptor to promote hepatocellular carcinoma progression

Wormser L, Kojic S, Fritz V, Benkert M, Düll M, Waldner M, Siebler J, Trebicka J, Hellerbrand C, Neurath M, Boßerhoff AK, Dietrich P (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Journal of Pathology Wiley

DOI: 10.1002/path.70115

Abstract

Pancreatic polypeptide (PP) and neuropeptide Y4 receptor (Y4R) are part of a conserved system that is involved in appetite regulation, gastrointestinal functions, and energy homeostasis. Experimental evidence suggests that PP-Y4R signaling might play a role in various extrahepatic cancer types, but the exact mechanisms remain unclear. Moreover, the potential role of PP-Y4R crosstalk in hepatocellular carcinoma (HCC) was unknown and has been addressed in this study. We found that the ligand (PP) and the receptor (Y4R) were markedly overexpressed in HCC cells and in patient-derived tissues, which was correlated with a poor prognosis. Mechanistically, we found that PP promoted migration of HCC cells mediated via activation of extracellular signal-regulated kinase (ERK) signaling. Knockdown of Y4R or pharmacological inhibition of Y4R decreased migration, clonogenicity, and proliferation of HCC cells and induced a G1-cell cycle arrest and cellular senescence. Conversely, activation of the PP-Y4R axis was sufficient to overcome both spontaneous and sorafenib-induced senescence, which was mediated by ERK signaling. Our study provides novel insights into the pro-tumorigenic roles of PP and Y4R in HCC, indicating that PP-Y4R crosstalk might represent a potential novel therapeutic target. © 2026 The Pathological Society of Great Britain and Ireland.

Authors with CRIS profile

Laura Wormser Lehrstuhl für Biochemie und Molekulare Medizin Sabrina Kojic Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Valerie Fritz Lehrstuhl für Biochemie und Molekulare Medizin Matthias Benkert Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Miriam Düll Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Maximilian Waldner Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Jürgen Siebler Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Claus Hellerbrand Professur für Biochemie und Molekulare Pathobiologie Markus Neurath Lehrstuhl für Innere Medizin I (Medizin 1) Anja Katrin Boßerhoff Lehrstuhl für Biochemie und Molekulare Medizin Peter Dietrich Lehrstuhl für Biochemie und Molekulare Medizin

Involved external institutions

Universität Münster (ehem. Westfälische Wilhelms-Universität (WWU)) DE Germany (DE)

How to cite

APA:

Wormser, L., Kojic, S., Fritz, V., Benkert, M., Düll, M., Waldner, M.,... Dietrich, P. (2026). Pancreatic polypeptide interacts with neuropeptide Y4 receptor to promote hepatocellular carcinoma progression. Journal of Pathology. https://doi.org/10.1002/path.70115

MLA:

Wormser, Laura, et al. "Pancreatic polypeptide interacts with neuropeptide Y4 receptor to promote hepatocellular carcinoma progression." Journal of Pathology (2026).

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