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DOI: 10.1055/s-2008-1076695
© Georg Thieme Verlag KG Stuttgart · New York
Lack of Nuclear Expression of Hairy and Enhancer of Split-1 (HES1) in Pancreatic Endocrine Tumors
Publikationsverlauf
received 29.10.2007
accepted 05.02.2008
Publikationsdatum:
19. Mai 2008 (online)
![](https://www.thieme-connect.de/media/hmr/200805/lookinside/thumbnails/10.1055-s-2008-1076695-1.jpg)
Abstract
The Notch signaling cascade plays a vital role in the proliferation and differentiation of cells during pancreatic development. Cell line experiments have suggested the involvement of Notch signaling in pancreatic endocrine tumorigenesis. We investigated the expression of NOTCH1, HES1, HEY1 and ASCL1 in pancreatic endocrine tumors and compared the data to tumor phenotype including hormone production, heredity, and WHO classification. Real-time quantitative PCR and immunohistochemistry were performed on samples of 26 pancreatic endocrine tumors. For comparison, 10 specimens of macroscopically normal pancreas were analyzed using immunohistochemistry. The subcellular localization of proteins was determined. Neither hormone production, nor heredity, or WHO classification was found to be associated with the expression of these proteins. There were discrepancies between mRNA and protein expression levels. All tumors displayed ASCL1 immunoreactivity. HES1 immunoreactivity was lacking altogether in 46% of the tumors, and in the remaining lesions its expression was weak and confined to the cytoplasm. In the nontumorous pancreatic endocrine cells, weak nuclear expression of HES1 as well as of HEY1 and NOTCH1 was observed. There was a significant positive correlation between NOTCH1 and HES1 mRNA levels, but no indication that HES1 was inhibiting ASCL1 transcription was found. No nuclear expression of HES1 was found in the tumors. This lack of nuclear expression of HES1 may contribute to the abundance of ASCL1 and to tumorigenesis in the endocrine pancreas.
Key words
ASCL1 - NOTCH1 - HEY1 - MEN1 - tumorigenesis
References
- 1 Stalberg P, Santesson M, Ekeblad S, Lejonklou MH, Skogseid B. Recognizing genes differentially regulated in vitro by the multiple endocrine neoplasia type 1 (MEN1) gene, using RNA interference and oligonucleotide microarrays. Surgery. 2006; 140 921-929
- 2 Kunnimalaiyaan M, Yan S, Wong F, Zhang YW, Chen H. Hairy Enhancer of Split-1 (HES-1), a Notch1 effector, inhibits the growth of carcinoid tumor cells. Surgery. 2005; 138 1137-1142
- 3 Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol. 2003; 194 237-255
- 4 Pompa JL de la, Wakeham A, Correia KM, Samper E, Brown S, Aguilera RJ, Nakano T, Honjo T, Mak TW, Rossant J, Conlon RA. Conservation of the Notch signalling pathway in mammalian neurogenesis. Development. 1997; 124 1139-1148
- 5 Ishibashi M, Ang SL, Shiota K, Nakanishi S, Kageyama R, Guillemot F. 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
- 6 Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, Hrabe de Angelis M, Lendahl U, Edlund H. Notch signalling controls pancreatic cell differentiation. Nature. 1999; 400 877-881
- 7 Jensen J. Gene regulatory factors in pancreatic development. Dev Dyn. 2004; 229 176-200
- 8 Pomplun D, Florian S, Schulz T, Pfeiffer AFH, Ristow M. Alterations of pancreatic beta-cell mass and islet number due to Ins2-controlled expression of Cre recombinase: RIP-Cre revisted; part 2. Horm Metab Res. 2007; 39 336-340
- 9 Sippel RS, Carpenter JE, Kunnimalaiyaan M, Chen H. The role of human achaete-scute homolog-1 in medullary thyroid cancer cells. Surgery. 2003; 134 866-871 , ; discussion 871-863
- 10 Sriuranpong V, Borges MW, Strock CL, Nakakura EK, Watkins DN, Blaumueller CM, Nelkin BD, Ball DW. Notch signaling induces rapid degradation of achaete-scute homolog 1. Mol Cell Biol. 2002; 22 3129-3139
- 11 Jiang SX, Kameya T, Asamura H, Umezawa A, Sato Y, Shinada J, Kawakubo Y, Igarashi T, Nagai K, Okayasu I. hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors. Mod Pathol. 2004; 17 222-229
- 12 Sriuranpong V, Borges MW, Ravi RK, Arnold DR, Nelkin BD, Baylin SB, Ball DW. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res. 2001; 61 3200-3205
- 13 Harper JA, Yuan JS, Tan JB, Visan I, Guidos CJ. Notch signaling in development and disease. Clin Genet. 2003; 64 461-472
- 14 Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann NY Acad Sci. 2004; 1014 13-27
- 15 Heid CA, Stevens J, Livak KJ, Williams PM. Real time quantitative PCR. Genome Res. 1996; 6 986-994
- 16 Sasai Y, Kageyama R, Tagawa Y, Shigemoto R, Nakanishi S. Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Dev. 1992; 6 2620-2634
- 17 Hirata H, Yoshiura S, Ohtsuka T, Bessho Y, Harada T, Yoshikawa K, Kageyama R. Oscillatory expression of the bHLH factor Hes1 regulated by a negative feedback loop. Science. 2002; 298 840-843
- 18 Georgia S, Soliz R, Li M, Zhang P, Bhushan A. p57 and Hes1 coordinate cell cycle exit with self-renewal of pancreatic progenitors. Dev Biol. 2006; 298 22-31
- 19 Murata K, Hattori M, Hirai N, Shinozuka Y, Hirata H, Kageyama R, Sakai T, Minato N. Hes1 directly controls cell proliferation through the transcriptional repression of p27Kip1. Mol Cell Biol. 2005; 25 4262-4271
- 20 Cupisti K, Hoppner W, Dotzenrath C, Simon D, Berndt I, Roher HD, Goretzki PE. Lack of MEN1 gene mutations in 27 sporadic insulinomas. Eur J Clin Invest. 2000; 30 325-329
- 21 Chin MT, Maemura K, Fukumoto S, Jain MK, Layne MD, Watanabe M, Hsieh CM, Lee ME. Cardiovascular basic helix loop helix factor 1, a novel transcriptional repressor expressed preferentially in the developing and adult cardiovascular system. J Biol Chem. 2000; 275 6381-6387
- 22 Iso T, Chung G, Hamamori Y, Kedes L. HERP1 is a cell type-specific primary target of Notch. J Biol Chem. 2002; 277 6598-6607
- 23 Kokubo H, Lun Y, Johnson RL. Identification and expression of a novel family of bHLH cDNAs related to Drosophila hairy and enhancer of split. Biochem Biophys Res Commun. 1999; 260 459-465
- 24 Leimeister C, Externbrink A, Klamt B, Gessler M. Hey genes: a novel subfamily of hairy- and Enhancer of split related genes specifi-cally expressed during mouse embryogenesis. Mech Dev. 1999; 85 173-177
- 25 Nakagawa O, Nakagawa M, Richardson JA, Olson EN, Srivastava D. HRT1, HRT2, and HRT3: a new subclass of bHLH transcription factors marking specific cardiac, somitic, and pharyngeal arch segments. Dev Biol. 1999; 216 72-84
- 26 Kunisch M, Haenlin M, Campos-Ortega JA. Lateral inhibition mediated by the Drosophila neurogenic gene delta is enhanced by proneural proteins. Proc Natl Acad Sci USA. 1994; 91 10139-10143
- 27 Borges M, Linnoila RI, Velde HJ van de, Chen H, Nelkin BD, Mabry M, Baylin SB, Ball DW. An achaete-scute homologue essential for neuroendocrine differentiation in the lung. Nature. 1997; 386 852-855
Correspondence
B. SkogseidMD, PhD
Department of Medical Sciences
Uppsala University
75185 Uppsala
Sweden
Telefon: +46/18/611 00 00
Fax: +46/18/55 36 01
eMail: Britt.Skogseid@medsci.uu.se