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 (K/K) 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 (K/K) 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.

Evaluation of NKX2-2 expression in round cell sarcomas and other tumors with EWSR1 rearrangement: imperfect specificity for Ewing sarcoma

“…[4][5][6] A member of the ETS family and a marker of endothelial differentiation, FLI-1 appears less sensitive for Ewing sarcoma than CD99 and is also expressed in various other round cell tumors including neuroblastoma, lymphoma, synovial sarcoma, rhabdomyosarcoma, desmoplastic small round cell tumor, Merkel cell carcinoma, and small cell carcinoma. 7 NKX2-2, a homeodomain-containing transcription factor involved in neuronal development and glial/neuroendocrine differentiation, 8,9 is a downstream target of EWSR1-FLI1 oncogenic signaling in Ewing sarcoma. 10 In recent times, NKX2-2 has been reported as a diagnostically useful immunohistochemical marker for Ewing sarcoma.…”

The homeobox NKX and Neoplasms in Digestive system: a systematic review.

“…Wang et al carried out a series of studies to ascertain the role of NKX2.2 in normal and neoplastic gut. First, their team demonstrated the distribution of NKX2.2 expression in normal human gut tissue is similar to that in mice, supporting the use of the mouse as a model for studying NE differentiation in the human gut [26] . Then with the use of NKX2.2 mutant mice, the team evaluated NKX2.2 expression in embryonic and adult mouse proximal small intestine by immunofluorescent (IF) analysis, and gave a result that NKX2.2 expression was seen at later embryonic (E) time points and persisted in the adult intestine, which suggested that NKX2.2 is transiently expressed in immature and/or newly differentiated cells.…”

“…Overall, the researcher detected nuclear expression of NKX2.2 in 83% (24/29) of welldifferentiated GI-NETs, including NETs of the stomach, duodenum, ampulla of Vater, pancreas, ileum, and colon. From the readily detection of intense NKX2.2 expression in most human NETs from GI sites, the conclusion were drawn that NKX2.2 is a novel NET-GI marker [26] . For more extended achievement, Wang et al selected 13 previously undescribed patients with BP-TCs identified at UCSF to ascertain whether the lack of NKX2.2 expression in BP-TCs is useful to distinguish BP-from GI-NETs, while normal human pancreas and a well-differentiated NET of pancreas and one of the ileum were used as controls.…”

“…According to several studies, the homeodomain transcription factor NKX2.2 are thought to regulate development of gut serotonin cells, play important roles in differentiation of normal and neoplastic gut [26] , cooperate with FEV and ASC11 in promoting tumor progression in SI-NETs [28] , and be a highly sensitive and specific marker of GI-NETs to distinguish BP-NETs [27] . Over last 30 years, the incidence of NETs were still increased and its survival rates were still unsatisfied.…”

The Diagnosis and Management of Neuroendocrine Carcinoma of Unknown Primary

“…CDX2 is specific for GI-NETs, but it also has low and variable sensitivity and is not a good marker for pancreatic NETs (Saqi, Alexis et al 2005;Lin, Saad et al 2007;Srivastava and Hornick 2009). NKX2.2 is a highly sensitive and specific marker for GI-NETs, including NETs of the stomach, duodenum, ampulla of Vater, pancreas, ileum, and colon (Wang, Gallego-Arteche et al 2009;Wang, Iezza et al 2010). In the future, use of a panel of markers may be particularly informative (Srivastava and Hornick 2009).…”