Amyloid precursor-like protein 1 is differentially upregulated in neuroendocrine tumours of the gastrointestinal tract

Abstract

We have examined the global gene expression profile of small intestinal carcinoids by microarray analysis. High expression of a number of genes was found including amyloid precursor-like protein 1 (APLP1). Quantitative real-time PCR and western blot analysis demonstrated higher expression of APLP1 in carcinoid metastases relative to primary tumours indicating a role of APLP1 in tumour dissemination. Tissue microarray analysis of gastroentero-pancreatic tumours demonstrated a high frequency of APLP1 expression and a low frequency of APLP2 expression in neuroendocrine (NE) tumours when compared with non-NE tumours at the same sites. Meta-analysis of gene expression data from a large number of tumours outside the gastrointestinal tract confirmed a correlation between APLP1 expression and NE phenotype where high expression of APLP1 was accompanied by downregulation of APLP2 in NE tumours. Cellular localization of APLP1, APLP2 and amyloid precursor protein (APP) in carcinoid cells (GOT1) by confocal microscopy demonstrated partial co-localization with synaptophysin. This suggests that the APP family of proteins is transported to the cell membrane by synaptic microvesicles and that they may influence tumour cell adhesion and invasiveness. We conclude that APLP1 is differentially upregulated in gastrointestinal NE tumours and that APLP1 may be important for the dissemination of small intestinal carcinoids. Identification of APLP1 in NE tumours offers a novel target for treatment and may also serve as a tumour-specific marker.

Different gene expression profiles in metastasizing midgut carcinoid tumors

“…These genes have not, to our knowledge, been detected in other microarray studies. Two microarray studies have compared the gene expression in midgut carcinoid tumors with normal mucosa and/or normal EC cells (Kidd et al 2006, Leja et al 2009) and one with a cell line from a liver metastasis (GOT1; Arvidsson et al 2008). In the work by Leja et al (2009), NKX23 had a lower expression level in liver metastases compared with primary tumors, and this is in accordance with the findings in this study; however, this has not been verified by RT-qPCR.…”

“…There are some suggestions of novel genes (PNMA2, SPOCK1, SERPINA10, GRIA2, GRP112, OR51E1, CXCL14, NKX23, NAP1L1, MAGE-D2, MTA-1, and APLP1) that may be of importance for tumorigenesis, but their role in the development of midgut carcinoid tumors is still unknown (Kidd et al 2006, Arvidsson et al 2008, Leja et al 2009). In two of the microarrays, the gene expression in tumor tissues was compared with normal EC cells and/or bowel mucosa (Kidd et al 2006, Leja et al 2009, and in one microarray, the gene expression was compared with a cell line (GOT1; Arvidsson et al 2008). It is difficult to extract normal EC cells from the bowel mucosa, because these cells are scattered throughout the gastrointestinal mucosa, and isolating these cells will result in contamination from surrounding tissue.…”

Cytotoxic Effects of Valproic Acid on Neuroendocrine Tumour Cells

“…The human small intestinal NET cell line GOT1 was maintained in RPMI-1640 medium supplemented with 5 μg/ml transferrin and 5 μg/ml insulin [24,25]. The human small intestinal NET cell line KRJ-I was cultured in HAMS F/12 medium [26].…”

Profiling of Ileal Carcinoids

“…Arvidsson et al [107] examined the global gene expression profile of ileal carcinoids in relation to a universal human reference RNA (URR). Tumors from 5 patients with distant disease were analyzed on a Swegene 27K DNA array.…”