Transmembrane protein tyrosine phosphatase IA-2 (ICA512) is expressed in human midgut carcinoids but is not detectable in normal enterochromaffin cells

Abstract

A potential upregulation of receptor type protein tyrosine phosphatase IA-2 (ICA512) expression was detected by differential display and investigated in midgut carcinoid tumours. Normal intestine tissue and tumour tissue from 13 midgut carcinoid patients were studied by in situ hybridisation using an IA-2 ribonucleotide probe and confocal microscopy using specific IA-2 antibodies. Previously, it had been shown that IA-2 is located in the secretory granules of virtually all neuroendocrine cells. However, we found that IA-2 was not detectable in resting normal enterochromaffin (EC) cells of the small intestine, while high expression of IA-2 mRNA and protein was confirmed in both primary and metastatic carcinoid tissue. This difference in expression was not observed with chromogranin A or serotonin, two secretory granule hormones known to be expressed in EC cells, indicating that IA-2 was seemingly not necessary for the basal production and packaging of these hormones. When comparing patients receiving biotherapy before operation with untreated patients, we found expression of IA-2 to be lower in tumours from patients that had been treated with a combination of -interferon and the somatostatin analogue, octreotide. There was no correlation between IA-2 expression and proliferation rates as measured by immunohistochemistry with antibodies against the Ki 67 antigen. Furthermore, we show that IA-2 is co-localised with serotonin in carcinoid tumours as well as in the pancreatic tumour cell line, BON1, which is interesting as serotonin secretion rate is presumably higher in tumour cells than in resting EC cells. Taken together, these findings may indicate a role for IA-2 in the later stages of the regulated secretory process.

Gene expression in midgut carcinoid tumors: Potential targets for immunotherapy

“…Protein expression of IA-2 and CDX-2 has been shown by other authors in midgut carcinoid tissue [12,19], and the expression has been further validated by our RNA analysis. We believe these proteins may be used as potential target antigens as well.…”

“…As expected, the genes encoding pivotal proteins in enterochromaffin cells such as CGA [11], PGP9.5 [14], Synaptophysin [15], TPH1 [16], VMAT1, and VMAT2 [17,18] were robustly expressed in midgut carcinoid tissue. We also confirmed the expression of IA-2 [12,13] and CDX-2 [19]. In addition, our analyses revealed expression of several genes in the tumor area that have previously not been described in midgut carcinoid tumors, such as: Amphiphysin [9,10], M2BP [20,21], MUC1 [22,23], SART-1 [26], Survivin [27,28], TROP-2 [29], GAGE-1,2,8 and GAGE-3-7b [30].…”

“…In this study we analyzed the expression of 32 target genes in order to define potential antigens suitable for cytotoxic T-cell (CTL) -mediated immunotherapy. Amphiphysin [9,10], Chromogranin A (CGA) [11], IA-2 [12,13], Protein gene product 9.5 (PGP9.5) [14], Synaptophysin [15], Tryptophan hydroxylase (TPH) 1 [16], and Vesicular monoamine transporters 1 and 2 (VMAT1, VMAT2) [17,18] represent proteins that are considered essential for enterochromaffin cell function, i.e. tissuerestricted differentiation antigens.…”

Identification of a Five-mRNA Signature as a Novel Potential Prognostic Biomarker for Glioblastoma by Integrative Analysis

“…PTPRN has been identified as an autoantigen that reacts with insulin-dependent diabetes mellitus (IDDM) patient sera (Lan et al, 1994;Acevedo-Calado et al, 2019). Only a few studies have reported a relationship with tumors, such as human midgut carcinoids and small cell lung cancer (Cunningham et al, 2000;Xu et al, 2016). Neuromedin B (NMB) is a member of the bombesin-like family of neuropeptides (Jensen et al, 2008).…”

Loss of the Transcriptional Repressor PAG-3/Gfi-1 Results in Enhanced Neurosecretion that is Dependent on the Dense-Core Vesicle Membrane Protein IDA-1/IA-2

“…We have shown previously that IA-2 is strongly expressed in many small cell lung carcinoma (SCLC) cells with a neuroendocrine phenotype, but not in non-neuroendocrine carcinomas [63]. In fact, IA-2 is expressed in many other, if not all, human neuroendocrine cancer cells examined such as insulinoma [64] and serotonin-secreting tumors of the midgut [65]. Our current results suggest that deregulation of Gfi-1/PAG-3 in neuroendocrine neoplastic disease may severely alter IA-2-related homeostatic control.…”