Endocrine Abstracts (2018) 56 P133 | DOI: 10.1530/endoabs.56.P133

Presence and functional role of KiSS/KiSS-R system in pancreatic neuroendocrine tumors (panNETs) and its relationship with clinical features and tumor behavior

Emilia Alors-Perez1,2,3,4, Sergio Pedraza-Arevalo1,2,3,4, Aura Herrera-Martinez1,2,5, Angel J Diaz-Perez6, Teresa Caro1,2,7, Raquel Serrano-Blanch1,2,8, Rafael Sanchez-Sanchez1,2,7, María Angeles Galvez-Moreno1,2,5, Justo P Castaño-Fuentes1,2,3,4, Raul M Luque1,2,3,4 & Antonio J Martinez-Fuentes1,2,3,4

1Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain; 2Reina Sofia University Hospital (HURS), Córdoba, Spain; 3Department of Cell Biology, Physiology and Immunology, University of Cordoba, Córdoba, Spain; 4CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Córdoba, Spain; 5Endocrinology and Nutrition Service, HURS, Córdoba, Spain; 6Endocrinology Service, San Carlos Clinical Hospital, Madrid, Spain; 7Pathology Service (HURS), Córdoba, Spain; 8Medical Oncology Service, HURS, Córdoba, Spain.

Pancreatic neuroendocrine tumors (panNETs) are the second most common neoplasm of the pancreas. panNETs arise from cells of the pancreatic islets and comprise a diverse and heterogeneous group of neoplasms. This hampers their systematic study, and the identification of common molecular signatures that might facilitate a better diagnosis of the disease, and the development of efficient therapeutic approaches. Indeed, there are no clinical, biochemical, anatomopathological, immunohistochemical or molecular features capable to predict either tumor prognosis or postsurgical treatment for panNETs. Current evidence indicate that certain regulatory systems composed of G-protein coupled receptors and their ligands could play a crucial role in the development and/or progression of different endocrine-related tumors. In this line, several studies have shown that the KiSS/KiSSR system is present in certain tumor types where it exerts antitumoral actions. Accordingly, the goal of this study was to determine the presence of this system in human panNET tissue samples by qPCR (n=46, including tumor and non-tumor adjacent regions) and to analyze its relationship with several tumor distinctive clinical features related to tumor prognosis. In addition, we sought to study the potential functional role of this regulatory system in panNETs using BON1 cell line. Firstly, we found that expression levels of KiSS were higher and of KiSSR lower in panNET tissues compared to its adjacent non-tumor tissues. Moreover, KiSS expression appeared to be upregulated in panNET samples from patients harboring metastatic disease, whereas KiSSR expression was significantly lower when compared to samples from non-metastatic patients. In addition, functional assays demonstrated that kisspeptin10 significantly modulated both cell proliferation and migration processes in BON1. Interestingly, blockade of KiSSR using a KiSS1R-antagonist (kisspeptin234) evoked a significant increase in the proliferation rate of panNET cells after 24 and 48 h, while did not change cell migration capacity. Finally, combined administration of kisspeptin10 and KiSS1R-antagonist significantly reduced BON1 cell proliferation and migration after 24 h exposure, suggesting that KiSS1R-antagonist did not counteract the antitumoral action of KiSS1 in this experimental setting. Ongoing analyses indicate that the antitumor actions of KiSS1 on panNET cell line involve the modulation of various signaling pathways and different molecular mechanisms. Altogether, our results provide original evidence for the presence and functional activity of the KiSS/KiSSR system in panNETs, suggesting its potential role in the development and/or progression of this pathology, and paving the way to explore its value as a novel biomarker and/or therapeutic target in panNETs.