title: Differential expression and tumorigenic function of neurotensin receptor 1 in neuroendocrine tumor cells.
abstract: Neurotensin (NTS), localized predominantly to the small bowel, stimulates the growth of a variety of cancers, including neuroendocrine tumors (NETs), mainly through its interaction with the high-affinity NTS receptor 1 (NTSR1). Here, we observed increased expression of NTSR1 in almost all tested clinical NET samples, but not in normal tissues. Through RT-PCR analysis, we found that the expression of NTSR1 and NTSR2 was either variable (NTSR1) or absent (NTSR2) in human NET cell lines. In contrast, NTSR3 and NTS were expressed in all NET cells. Treatment with 5-aza-2'-deoxycytidine, a demethylating agent, increased levels of NTSR1 and NTSR2 suggesting that DNA methylation contributes to NTSR1/2 expression patterns, which was confirmed by methylation analyses. In addition, we found that knockdown of NTSR1 decreased proliferation, expression levels of growth-related proteins, and anchorage-independent growth of BON human carcinoid cells. Moreover, stable silencing of NTSR1 suppressed BON cell growth, adhesion, migration and invasion. Our results show that high expression of NTSR1 is found in clinical NETs and that promoter methylation is an important mechanism controlling the differential expression of NTSR1 and silencing of NTSR2 in NET cells. Furthermore, knockdown of NTSR1 in BON cells suppressed oncogenic functions suggesting that NTSR1 contributes to NET tumorigenesis.
authors: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors: Ji Tae
authors: JT
authors: Kim
authors: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Surgery, University of Kentucky, Lexington, KY, USA.
authors: Jing
authors: J
authors: Li
authors: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Surgery, University of Kentucky, Lexington, KY, USA.
authors: Jun
authors: J
authors: Song
authors: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, USA.
authors: Eun Y
authors: EY
authors: Lee
authors: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors: Heidi L
authors: HL
authors: Weiss
authors: Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA.
authors: Courtney M
authors: CM
authors: Townsend
authors: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Surgery, University of Kentucky, Lexington, KY, USA.
authors: B Mark
authors: BM
authors: Evers
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000737:chemistry; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D000077209:Decitabine; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D009361:Neoplasm Invasiveness; D018358:Neuroendocrine Tumors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D018028:Receptors, Neurotensin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C490985:NTSR2 protein, human; D034741:RNA, Small Interfering; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D000077209:Decitabine; D001374:Azacitidine
keywords: cell growth; cell migration; neuroendocrine tumor; neurotensin receptor 1; promoter methylation