Differential Expression and Tumorigenic Function of Neurotensin Receptor 1 in Neuroendocrine Tumor Cells

Authors

Ji Tae Kim, University of KentuckyFollow
Jing Li, University of KentuckyFollow
Jun Song, University of KentuckyFollow
Eun Y. Lee, University of KentuckyFollow
Heidi L. Weiss, University of KentuckyFollow
Courtney M. Townsend, University of Texas Medical Branch
B. Mark Evers, University of KentuckyFollow

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.

Document Type

Article

Publication Date

9-29-2015

Notes/Citation Information

Published in Oncotarget, v. 6, no. 29, p. 26960-26970.

Copyright @ 2016 Impact Journals, LLC.

Licensed under a Creative Commons Attribution 3.0 License.

Digital Object Identifier (DOI)

http://dx.doi.org/10.18632/oncotarget.4745

Funding Information

This research was supported by a grant from the NIH (R37 AG010885) and the Markey Cancer Foundation.

We further acknowledge support from the the Biospecimen and Tissue Procurement and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center (supported by NCI grant P30CA177558)

Repository Citation

Kim, Ji Tae; Li, Jing; Song, Jun; Lee, Eun Y.; Weiss, Heidi L.; Townsend, Courtney M.; and Evers, B. Mark, "Differential Expression and Tumorigenic Function of Neurotensin Receptor 1 in Neuroendocrine Tumor Cells" (2015). Markey Cancer Center Faculty Publications. 56.
https://uknowledge.uky.edu/markey_facpub/56