NUP153 in neuroendocrine tumors
Nucleoporins (NUPs) constitute the nuclear pore complex (NPC) and are essentially involved in nuclear transport, chromatin organization, and context-dependent gene regulation. However, the role of NUPs in neuroendocrine (tumor)biology and related diagnostic potential is poorly defined. In this study, we comparatively analyzed immunohistochemical expression patterns of NUP98 and NUP153 (sharing structural and functional similarities) across a large variety of human tissues and tumors (total N > 600), with a focus on neuroendocrine neoplasms (NENs (n = 361)). While both NUPs showed a nuclear rim accentuated staining pattern, NUP98 exhibited ubiquitous and NUP153 a striking cell- and tissue/tumor-type-dependent immunoreactivity. More specifically, NUP153 immunoreactivity was consistently detectable in neuroendocrine tissues (e.g. pancreatic islets) and retained in neuroendocrine tumors (NETs) of the pancreas, lung, appendix, and small intestine, but absent in neuroendocrine carcinomas (NECs) and non-neuroendocrine carcinomas. Loss of NUP153 staining correlated with higher tumor grade, increased Ki67(MIB1)-proliferation rate, and poorer clinical outcomes in pancreatic and pulmonary NENs. Further analyses revealed that NUP153 mRNA and total protein levels were not significantly different between NETs and NECs, as evaluated by quantitative PCR and targeted proteomics. Differential isoform usage was ruled out by PCR and sequencing as another possible explanation for the discriminative immunohistochemical findings. Finally, a high density of post-translational modifications (PTMs) within the antibody recognition region could be discovered and indicated PTM-dependent detection of the epitope as the likely cause of differential staining.  Collectively, our findings suggest that NUP153 is a differentiation-dependent and PTM-sensitive immunohistochemical marker in NENs with diagnostic and prognostic potential.