RSUME is implicated in tumorigenesis and metastasis of pancreatic neuroendocrine tumors

Abstract

The factors triggering pancreatic neuroendocrine tumor (PanNET) progression are largely unknown. Here we investigated the role and mechanisms of the sumoylation enhancing protein RSUME in PanNET tumorigenesis. Immunohistochemical studies showed that RSUME is strongly expressed in normal human pancreas, in particular in β-cells. RSUME expression is reduced in insulinomas and is nearly absent in other types of PanNETs suggesting a role in PanNET tumorigenesis. In human pancreatic neuroendocrine BON1 cells, RSUME stimulates hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A), which are key components of tumor neovascularisation. In contrast, RSUME suppresses nuclear factor-κB (NF-κB) and its target interleukin-8 (IL-8). Correspondingly, PanNET cells with RSUME knockdown showed decreased HIF-1α activity and increased NF-κB and IL-8 production leading to a moderate reduction of VEGF-A release as reduced HIF-1α/VEGF-A production is partly compensated by NF-κB/IL-8-induced VEGF-A. Notably, RSUME stabilizes the tumor suppressor PTEN, which is frequently lost in PanNETs and whose absence is associated with metastasis formation. In vivo orthotopic transplantation of PanNET cells with or without RSUME expression into nude mice showed that PanNETs without RSUME have reduced PTEN expression, grow faster and form multiple liver metastases. In sum, RSUME differentially regulates key components of PanNET formation suggesting that the observed loss of RSUME in advanced PanNETs is critically involved in PanNET tumorigenesis, particularly in metastasis formation.

A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

“…Since Panc1 cells are highly invasive, these cells were used along with another non-motile PDAC cell line, Colo357, as controls in the migration assays. Panc1 cells are of ductal/exocrine origin; however, they possess some neuroendocrine features, such as expression of CgA and SSTR2 [64] and the potential to be transdifferentiated into insulin-producing cells [65][66][67][68].…”

Endocrine targets of hypoxia-inducible factors

“…Furthermore, RSUME, a RWD-containing protein that stabilizes and enhances HIF-1α expression is reduced in pancreatic endocrine tumors. In vivo orthotopic mice show that knockdown of RSUME enhances pancreatic endocrine tumor growth and liver metastasis (Wu et al 2016). Collectively, these studies show that HIF expression and microvessel density are increased in well-differentiated pancreatic endocrine tumors and are positively correlated with overall survival rate.…”

GEOFFREY HARRIS AWARD 2019: Translational research in pituitary tumours

“…The pituitary tumour cell from which RSUME was cloned showed increased tumorigenic and angiogenic potential when experimentally injected into nude mice with respect to a control GH3 stable cell line. Beside pituitary adenomas, RSUME was found to be expressed in other types of tumours with high angiogenic potential, among them gliomas (28) and pancreatic neuroendocrine tumours (29). Particularly, RSUME is expressed in tissues prone to tumour development in Von Hippel Lindau (VHL) syndrome and is upregulated in several tumours related to this disease (27,30).…”