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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-0540 Copyright © 2005 by The Endocrine Society Regulation of Neuroendocrine Differentiation in Gastrointestinal Carcinoid Tumor Cells by Notch SignalingEric K. Nakakura, Virote R. Sriuranpong, Muthusamy Kunnimalaiyaan, Edward C. Hsiao, Kornel E. Schuebel, Michael W. Borges, Ning Jin, Brendan J. Collins, Barry D. Nelkin, Herbert Chen1 and Douglas W. Ball1Department of Surgery (E.K.N.), University of California, San Francisco, California 94115; The Sidney Kimmel Comprehensive Cancer Center (V.R.S., K.E.S., M.W.B., N.J., B.J.C., B.D.N., D.W.B.) and Departments of Medicine (E.C.H., D.W.B.), and Surgery (B.J.C.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231; and Department of Surgery (M.K., H.C.), University of Wisconsin Medical School, and the University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792 Address all correspondence and requests for reprints to: Eric K. Nakakura, 1600 Divisadero Street, Room A-724, San Francisco, California 94115. E-mail: NakakuraE{at}surgery.ucsf.edu. Context: Gastrointestinal (GI) carcinoid tumors elaborate serotonin and other vasoactive substances, causing the carcinoid syndrome. Based on developmental biology data, we hypothesized that basic helix-loop-helix transcription factors, including achaete-scute complex homolog-like 1 (Ascl1)/hASH1, and the Notch signaling pathway might regulate the neuroendocrine phenotype in GI carcinoids. Objective: The aim of this study was to evaluate expression of developmental transcription factors and Notch signaling components in GI carcinoids and model their interaction in a relevant GI carcinoid cell line. Design: Fourteen GI carcinoid tumor specimens, five paired adjacent normal tissues, fetal tissues, and tumor cell lines were analyzed by RT-PCR and immunoblot. BON carcinoid cells were further analyzed after Notch overexpression for neuroendocrine marker expression, serotonin production, and growth. Setting: The study was conducted in an academic referral center. Patients or Other Participants: Deidentified archival pathology specimens were examined. Results: Among a panel of six developmental transcription factors tested, only Ascl1 mRNA was overexpressed compared with surrounding normal tissue (seven of 10 GI carcinoid tumors and in BON cells, none of five normal tissues). Ascl1 protein was also expressed in four of four carcinoid tumors and BON cells). Notch pathway ligands, receptors, and downstream effectors were widely expressed in tumor and normal specimens. Overexpression of activated Notch1 in BON cells led to induction of the Notch effector hairy and enhancer of split 1 (Hes1), loss of Ascl1, reductions in neuron-specific enolase, synaptophysin, and chromogranin A, and most significantly, an 89% decrease in serotonin concentration and equivalent reductions in serotonin-reactive cells and repression of tryptophan hydroxylase 1 mRNA. Conclusions: The Notch signaling pathway is a significant regulator of neuroendocrine differentiation and serotonin production in GI carcinoid tumors. This article has been cited by other articles:
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