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2001 Abstract: 1795 Regulation of the Neuroendocrine Phenotype in Pancreatic Carcinoid Tumor Cells

2001 Digestive Disease Week

# 1795 Regulation of the Neuroendocrine Phenotype in Pancreatic Carcinoid Tumor Cells
Eric K. Nakakura, Virote Sriuranpong, Michael W. Borges, Neil Watkins, Barry D. Nelkin, Douglas W. Ball, Herbert Chen, Baltimore, MD, Madison, WI

Gastrointestinal carcinoid tumors exhibit characteristic neuroendocrine (NE) features capable of promoting tumor growth and virulence via autocrine growth loops and ectopic hormone production. However, the genetic pathways underlying NE differentiation in GI carcinoid tumors remain unknown. Previously, we have shown that hASH1, a proneural transcription factor, is expressed in small cell lung cancers (SCLC) and is required for maintenance of the NE phenotype. In SCLC, hASH1 expression is regulated by the Notch signaling pathway, involving the transcription factor HES-1. We hypothesized that hASH1 and Notch signaling might also function to regulate the NE phenotype in GI carcinoid tumors.

Methods: Expression of hASH1 and HES-1 as well as the NE markers neuron-specific enolase (NSE) and synaptophysin (Syn) were evaluated in the human pancreatic carcinoid cell line BON by Western blot analysis. Recombinant adenoviruses were used to overexpress Notch1 or b-galactosidase (control) in BON cells.

Results: High constitutive expression of hASH1 protein was detected in BON cells but not in two pancreatic adenocarcinoma cell lines (BxPC-3, Capan-2). Overexpression of Notch1 in BON cells led to induction of HES-1 protein, a negative regulator of hASH1 expression. Increased HES-1 levels were associated with a complete loss of hASH1 protein by one day post-infection with Notch1. By two days after Notch1 infection, expression of Syn protein was dramatically reduced. Similarly, NSE protein levels in BON cells progressively declined over the course of three days following Notch1 infection. Overexpression of b-galactosidase in BON cells had no effect on HES-1, hASH1, Syn, or NSE protein expression.

Conclusions: We show that hASH1, a transcription factor essential for NE differentiation in certain contexts, is highly expressed in the pancreatic carcinoid cell line BON. Significantly, hASH1 was not detected in two pancreatic adenocarcinoma cell lines. We also demonstrate that the Notch signaling pathway is intact in BON cells, leading to rapid extinguishing of hASH1 expression and subsequent depletion of NE markers. Our studies provide a molecular basis for potential strategies aimed toward manipulating Notch signaling in GI carcinoid tumors as a means to regulate the prominent NE phenotype that is central to their pathogenesis.

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