title: Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors.
abstract: 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.
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Wang
authors.forename: Emerick
authors.initials: E
authors.lastname: Gallego-Arteche
authors.forename: Gioia
authors.initials: G
authors.lastname: Iezza
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Yuan
authors.forename: Mary R
authors.initials: MR
authors.lastname: Matli
authors.forename: Su-Pin
authors.initials: SP
authors.lastname: Choo
authors.forename: Marlene B
authors.initials: MB
authors.lastname: Zuraek
authors.forename: Ravi
authors.initials: R
authors.lastname: Gogia
authors.forename: Francis C
authors.initials: FC
authors.lastname: Lynn
authors.forename: Michael S
authors.initials: MS
authors.lastname: German
authors.forename: Emily K
authors.initials: EK
authors.lastname: Bergsland
authors.forename: David B
authors.initials: DB
authors.lastname: Donner
authors.forename: Robert S
authors.initials: RS
authors.lastname: Warren
authors.forename: Eric K
authors.initials: EK
authors.lastname: Nakakura
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D055098:Endocrine Cells / Q000166:cytology / Q000502:physiology; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D054439:Ghrelin / Q000378:metabolism; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000196:embryology; D007421:Intestine, Small / Q000166:cytology / Q000196:embryology; D051379:Mice; D008817:Mice, Mutant Strains; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D029961:Zebrafish Proteins
chemical_list: D054439:Ghrelin; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish