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.
Highlights
Neurotensin (NTS), a 13-amino acid peptide, functions as a primary neurotransmitter as well as a neuromodulator in the central nervous system (CNS) and as a hormone in the periphery [1,2,3]
There is emerging evidence that either NTS or NTS receptor 1 (NTSR1) can be utilized as a prognostic marker for various cancers due to aberrant expression noted in tumors and not detected in normal tissues, and that silencing of the genes can inhibit the tumorigenic activities in some cancer cells [15,16,17,18,19,20,21]
We showed that NTSR1 protein is not or barely detected in 12 normal tissues but is strongly expressed in 95% of clinical neuroendocrine tumors (NETs) samples (19 of 20 NETs)
Summary
Neurotensin (NTS), a 13-amino acid peptide, functions as a primary neurotransmitter as well as a neuromodulator in the central nervous system (CNS) and as a hormone in the periphery [1,2,3]. NTS contributes to numerous physiologic functions in the gastrointestinal (GI) tract including GI secretion, gut motility, and growth of various normal tissues [1, 2]. NTS stimulates the growth of several cancer types including neuroendocrine tumors (NETs) that, compared to other cancers, are increasing in incidence [1, 3, 4]. The actions of NTS are mediated through three receptors (i.e., NTSR1, NTSR2 and NTSR3/sortilin), named according to the order in which they were cloned [2, 3]. High-affinity NTSR1, which is found in various regions of the CNS, in the small and large intestine, and in a variety of solid tumors, is considered a predominant mediator of the effects of NTS on cell proliferation, migration, and invasion [3, 5]. Different from NTSR1 and NTSR2, which are G protein-coupled receptors, NTSR3/sortilin is a single transmembrane receptor, which binds various neurotrophic factors and neuropeptides and is not specific for NTS [3, 8]
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