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This Article Full Text Full Text (PDF) All Versions of this Article: ERC-08-0127v1 16/1/267    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wang, Y.-C. Articles by Nakakura, E. K Search for Related Content PubMed PubMed Citation Articles by Wang, Y.-C. Articles by Nakakura, E. K

¹ UCSF Helen Diller Family Comprehensive Cancer Center, Departments of² Surgery³ Pathology⁴ Medicine, University of California, San Francisco, California 94143, USA⁵ Hormone Research Institute, Diabetes Center, University of California, San Francisco, California 94143, USA

(Correspondence should be addressed to E K Nakakura at Division of Surgical Oncology, Department of Surgery, UCSF Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, A-724, San Francisco, California 94143-1932, USA; Email: eric.nakakura{at}ucsfmedctr.org)

The homeodomain transcription factor NKX2.2 is necessary for neuroendocrine (NE) differentiation in the central nervous system and pancreas. NE tumors derived from the gut are defined by their NE phenotype, which is used for diagnosis and contributes to tumorigenicity. We hypothesized that NKX2.2 is important for NE differentiation in normal and neoplastic gut. NKX2.2 and NE marker expression was investigated in the small intestine of embryonic and adult mice using immunofluorescence (IF). To determine the role of NKX2.2 in NE differentiation of the intestine, the phenotype of Nkx2.2 (–/–) mice was examined by IF and real-time (RT)-PCR. NKX2.2 and NE marker expression in human NE tumors of the gut and normal tissues were evaluated by immunohistochemistry and qRT-PCR. NKX2.2 expression was detected in the intervillus/crypt regions of embryonic and adult mouse intestine. Co-expression of Nkx2.2 with neurogenin3 (NEUROG3) and hormones was observed in the adult intestinal crypt compartment, suggesting NKX2.2 functions in NEUROG3-positive endocrine progenitors and newly differentiated endocrine cells. In the intestine of Nkx2.2 (–/–) mice, we found a dramatic reduction in the number of cells producing numerous hormones, such as serotonin, gastrin, cholecystokinin, somatostatin, glucagon-like peptide 1 (GLP-1), and secretin, but an increase in cells producing ghrelin. NKX2.2 was expressed in most (24 of 29) human NE tumors derived from diverse primary sites. We conclude NKX2.2 functions in immature endocrine cells to control NE differentiation in normal intestine and is expressed in most NE tumors of the gut, and is therefore a novel target of diagnosis for patients with gastrointestinal NE tumors.