American Association of Endocrine Surgeon| Volume 138, ISSUE 6, P1137-1142, December 2005

Hairy Enhancer of Split-1 (HES-1), a Notch1 effector, inhibits the growth of carcinoid tumor cells


      The Notch1-signaling pathway has been shown to regulate the differentiation and growth of carcinoid tumor cells. However, the molecules that mediate Notch1 signaling, as well as their potential roles in regulating the growth of carcinoid tumors, have not been characterized. We and others have shown previously that the transcription factor Hairy Enhancer of Split-1 (HES-1) is upregulated in response to Notch1 signaling, demonstrating that it is a Notch1 effector. We hypothesized that HES-1 may be the essential downstream factor in Notch1-mediated growth regulation of carcinoid tumors.


      H727 carcinoid tumor cells were transduced stably with a doxycycline-inducible HES-1 construct, creating H727-HES-1 cells. H727-TRE (vector-only control) and H727-HES-1 cells were then treated with varying concentrations of doxycycline to achieve increasing levels of HES-1 protein expression. Cell proliferation was determined with the use of a cell viability assay.


      Treatment of H727-HES-1 cells with increasing dosages of doxycycline resulted in dose-dependent increases in HES-1 protein by Western blot analysis. Importantly, induction of HES-1 in carcinoid tumor cells led to suppression of tumor cellular proliferation. Moreover, the degree of carcinoid growth inhibition appeared to be proportional to the level of HES-1 induction.


      HES-1 alone can regulate the growth of carcinoid tumor cells. Furthermore, these results suggest that HES-1 may be the critical downstream effector in the Notch1-signaling pathway.
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        • Sippel R.S.
        • Chen H.
        An update on carcinoid tumors.
        Problems in general surgery. 2003; 20: 125-133
        • Mansour J.C.
        • Chen H.
        Pancreatic endocrine tumors.
        J Surg Res. 2004; 120: 139-161
        • Van Gompel J.J.
        • Sippel R.S.
        • Warner T.F.
        • et al.
        Gastrointestinal carcinoid tumors: factors that predict outcome.
        World J Surg. 2004; 28: 387-392
        • Sriuranpong V.
        • Borges M.W.
        • Ravi R.K.
        • et al.
        Notch signaling induces cell cycle arrest in small cell lung cancer cells.
        Cancer Res. 2001; 61: 3200-3205
        • Kunnimalaiyaan M.
        • Traeger K.
        • Chen H.
        Conservation of the Notch1 signaling pathway in gastrointestinal carcinoid cells.
        American Journal of Physiology-GI and Liver. 2005; 289: G636-G642
        • Chen H.
        • Thiagalingam A.
        • Chopra H.
        • et al.
        Conservation of the Drosophila lateral inhibition pathway in human lung cancer: a hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression.
        Proc Natl Acad Sci U S A. 1997; 94: 5355-5360
        • Fisher A.
        • Caudy M.
        The function of hairy-related bHLH repressor proteins in cell fate decisions.
        Bioessays. 1998; 20: 298-306
        • Fisher A.L.
        • Ohsako S.
        • Caudy M.
        The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain.
        Mol Cell Biol. 1996; 16: 2670-2677
        • Sasai Y.
        • Kageyama R.
        • Tagawa Y.
        • et al.
        Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split.
        Genes Dev. 1992; 6: 2620-2634
        • Sippel R.S.
        • Carpenter J.E.
        • Kunnimalaiyaan M.
        • et al.
        Raf-1 activation suppresses neuroendocrine marker and hormone levels in human gastrointestinal carcinoid cells.
        Am J Physiol Gastrointest Liver Physiol. 2003; 285: G245-G254
        • Apelqvist A.
        • Li H.
        • Sommer L.
        • et al.
        Notch signalling controls pancreatic cell differentiation.
        Nature. 1999; 400: 877-881
        • Artavanis-Tsakonas S.
        • Rand M.D.
        • Lake R.J.
        Notch signaling: cell fate control and signal integration in development.
        Science. 1999; 284: 770-776
        • Shou J.
        • Ross S.
        • Koeppen H.
        • et al.
        Dynamics of notch expression during murine prostate development and tumorigenesis.
        Cancer Res. 2001; 61: 7291-7297
        • Jensen J.
        • Pedersen E.E.
        • Galante P.
        • et al.
        Control of endodermal endocrine development by Hes-1.
        Nat Genet. 2000; 24: 36-44
        • Sippel R.S.
        • Carpenter J.E.
        • Kunnimalaiyaan M.
        • et al.
        The role of human achaete-scute homolog-1 in medullary thyroid cancer cells.
        Surgery. 2003; 134: 866-871
        • Kageyama R.
        • Nakanishi S.
        Helix-loop-helix factors in growth and differentiation of the vertebrate nervous system.
        Curr Opin Genet Dev. 1997; 7: 659-665
        • Ishibashi M.
        • Sasai Y.
        • Nakanishi S.
        • et al.
        Molecular characterization of HES-2, a mammalian helix-loop-helix factor structurally related to Drosophila hairy and Enhancer of split.
        Eur J Biochem. 1993; 215: 645-652
        • Ishibashi M.
        • Moriyoshi K.
        • Sasai Y.
        • et al.
        Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system.
        EMBO J. 1994; 13: 1799-1805
        • Ishibashi M.
        • Ang S.L.
        • Shiota K.
        • et al.
        Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects.
        Genes Dev. 1995; 9: 3136-3148
        • Tomita K.
        • Ishibashi M.
        • Nakahara K.
        • et al.
        Mammalian Hairy and Enhancer of Split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis.
        Neuron. 1996; 16: 723-734
        • Castella P.
        • Sawai S.
        • Nakao K.
        • et al.
        HES-1 repression of differentiation and proliferation in PC12 cells: Role for the helix 3-helix 4 domain in transcription repression.
        Mol Cell Biol. 2000; 20: 6170-6183
        • Muller P.
        • Kietz S.
        • Gustafsson J.A.
        • et al.
        The anti-estrogenic effect of all-trans-retinoic acid on the breast cancer cell line MCF-7 is dependent on HES-1 expression.
        J Biol Chem. 2002; 277: 28376-28379