LAUSR

MEN1, which encodes menin protein, is the most frequently mutated gene in pancreatic neuroendocrine neoplasms (pNEN). Pleiotrophin (PTN) was reported being a downstream factor of menin and to promote metastasis in different tumor entities. In this study, the effect of menin and its link to PTN were assessed on features of pNEN cells and outcome of pNEN patients. The expression of menin and PTN in pNEN patient tissues were examined by qRT-PCR and western blot and compared to their metastasis status. Functional assays, including transwell migration/invasion and scratch wound healing assays, were performed on specifically designed CRISPR/Cas9-mediated MEN1-knockout (MEN1-KO) pNEN cell lines (BON1MEN1-KO and QGP1MEN1-KO ) to study the metastasis of pNEN. Among 30 menin negative pNEN patients, 21 revealed a strong protein expression of PTN. This combination was associated with metastasis and shorter disease-free survival. Accordingly, in BON1MEN1-KO and QGP1MEN1-KO cells, PTN protein expression was positively associated with enhanced cell migration and invasion, which could be reversed by PTN silencing. PTN is a predicting factor of metastatic behavior of menin-deficient-pNEN. In vitro, menin is able to both promote and suppress the metastasis of pNEN by regulating PTN expression depending on the tumoral origin of pNEN cells.