hide
Free keywords:
RSUME, RWDD3, PanNETs, angiogenesis, metastasis
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 beta-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-1 alpha (HIF-1 alpha) and vascular endothelial growth factor-A
(VEGF-A), which are key components of tumor neovascularisation. In
contrast, RSUME suppresses nuclear factor-kappa B (NF-kappa B) and its
target interleukin-8 (IL-8). Correspondingly, PanNET cells with RSUME
knockdown showed decreased HIF-1 alpha activity and increased NF-kappa B
and IL-8 production leading to a moderate reduction of VEGF-A release as
reduced HIF-1 alpha/VEGF-A production is partly compensated by NF-kappa
B/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.
