Differential expression and tumorigenic function of neurotensin receptor 1 in neuroendocrine tumor cells
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Ji Tae Kim1, Jing Li1,2, Jun Song1,2, Eun Y. Lee1,3, Heidi L. Weiss1, Courtney M. Townsend Jr4, B. Mark Evers1,2
1Markey Cancer Center, University of Kentucky, Lexington, KY, USA
2Department of Surgery, University of Kentucky, Lexington, KY, USA
3Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, USA
4Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
B. Mark Evers, e-mail: firstname.lastname@example.org
Keywords: neuroendocrine tumor, neurotensin receptor 1, promoter methylation, cell growth, cell migration
Received: April 20, 2015 Accepted: July 15, 2015 Published: July 27, 2015
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.
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