Endocrine Abstracts

Pancreatic neuroendocrine tumors (panNETs) comprise several neoplasms in which a precise diagnosis and therapeutic treatment are hampered by their diversity and heterogeneity which in turn, hind the identification of common molecular signatures and the development of efficient therapeutic approaches. Subsequently, there are no clinical, biochemical, anatomopathological, immunohistochemical or molecular features capable to currently predict either tumor prognosis or post-surgical treatment for panNETs. In this sense, the KiSS/KiSS-R regulatory system has been documented to be expressed and play anti-tumoral actions in different endocrine-related tumors. In fact, we have previously showed the presence of KiSS/KiSS-R system in human panNET, and analyzed its relationship with several tumor distinctive clinical features associated to tumor prognosis. Specifically, we reported a higher KiSS- and a lower KiSS-R expression in panNET tumor tissues compared to their adjacent non-tumor tissues. Furthermore, KiSS expression appeared to be up-regulated in panNET samples from patients harboring metastatic disease, whereas KiSS-R expression was significantly lower when compared to samples from non-metastatic patients. On the other hand, we also reported the potential functional role of this regulatory system in BON-1 pancreatic cell line. Thus, we documented that proliferation and migration processes were regulated upon kisspeptin-10 (kp-10) treatment in naïve and KiSS1-R overexpressing cells. Ongoing analyses indicate that the anti-tumor actions of KiSS/KiSS-R system in BON-1 panNET cell line and in xenograft tumors derived from KiSS1-R overexpressing cells, involve the modulation of various oncogenic signaling pathways and different molecular mechanisms. Thus, proteomic analysis reveals a clear and general decline in the phosphorylation level of several components of MAPK and AKT oncogenic pathways after kp-10 treatment in both in vitro and in vitro experimental settings being this effect sensitized in several proteins by the KiSS-R overexpression. Furthermore, transcriptomic studies in BON-1 cells show the up-regulation and down-regulation of different genes after kp-10 administration. An ulterior enrichment analysis (KEGG/Reactome) reveal that these deregulated genes are associated to relevant pathways involved in pancreatic cancer, endocrine resistance and cell cycle among others. Altogether, our results provide original evidence for the presence and functional activity of the KiSS/KiSS-R system in panNETs, suggesting its potential role in the development and/or progression of this devastating pathology, and paving the way to explore its value as a novel biomarker and/or therapeutic target in panNETs.

Fundings

This work was funded by Junta de Andalucía (PI-0077-2016, BIO-0139), MINECO (PID2019-105564RB-I00/FPU16-05059) and CIBERobn.