Neurotensin, a novel target of Wnt/β-catenin pathway, promotes growth of neuroendocrine tumor cells

Ji Tae Kim, Chunming Liu, Yekaterina Y. Zaytseva, Heidi L. Weiss, Courtney Townsend, B. Mark Evers

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Wnt/β-catenin signaling plays a pivotal role in regulating cell growth and differentiation by activation of the β-catenin/T-cell factor (TCF) complex and subsequent regulation of a set of target genes that have one or more TCF-binding elements (TBEs). Hyperactivation of this pathway has been implicated in numerous malignancies including human neuroendocrine tumors (NETs). Neurotensin (NT), an intestinal hormone, induces proliferation of several gastrointestinal (GI) cancers including cancers of the pancreas and colon. Here, we analyzed the human NT promoter in silico and found at least four consensus TBEs within the proximal promoter region. Using a combination of ChIP and luciferase reporter assays, we identified one TBE (located ∼900 bp proximal from the transcription start site) that was immunoprecipitated efficiently by TCF4-targeting antibody; mutation of this site attenuated the responsiveness to β-catenin. We also confirmed that the promoter activity and the mRNA and protein expression levels of NT were increased by various Wnt pathway activators and decreased by Wnt inhibitors in NET cell lines BON and QGP-1, which express and secrete NT. Similarly, the intracellular content and secretion of NT were induced by Wnt3a in these cells. Finally, inhibition of NT signaling suppressed cell proliferation and anchorage-independent growth and decreased expression levels of growth-related proteins in NET cells. Our results indicate that NT is a direct target of the Wnt/β-catenin pathway and may be a mediator for NET cell growth.

Original languageEnglish (US)
Pages (from-to)1475-1481
Number of pages7
JournalInternational Journal of Cancer
Volume136
Issue number6
DOIs
StatePublished - Mar 15 2015

Fingerprint

Catenins
Neuroendocrine Cells
Neurotensin
Wnt Signaling Pathway
Neuroendocrine Tumors
Growth
TCF Transcription Factors
Gastrointestinal Hormones
Gastrointestinal Neoplasms
Transcription Initiation Site
Tumor Cell Line
Luciferases
Pancreatic Neoplasms
Genetic Promoter Regions
Computer Simulation
Colonic Neoplasms
Cell Differentiation
Proteins
Cell Proliferation
Messenger RNA

Keywords

  • Neuroendocrine tumor cells
  • Neurotensin
  • Target gene
  • Wnt/β-catenin pathway

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Neurotensin, a novel target of Wnt/β-catenin pathway, promotes growth of neuroendocrine tumor cells. / Kim, Ji Tae; Liu, Chunming; Zaytseva, Yekaterina Y.; Weiss, Heidi L.; Townsend, Courtney; Evers, B. Mark.

In: International Journal of Cancer, Vol. 136, No. 6, 15.03.2015, p. 1475-1481.

Research output: Contribution to journalArticle

Kim, Ji Tae ; Liu, Chunming ; Zaytseva, Yekaterina Y. ; Weiss, Heidi L. ; Townsend, Courtney ; Evers, B. Mark. / Neurotensin, a novel target of Wnt/β-catenin pathway, promotes growth of neuroendocrine tumor cells. In: International Journal of Cancer. 2015 ; Vol. 136, No. 6. pp. 1475-1481.
@article{25321fc642084da6bbce134cf955f4e6,
title = "Neurotensin, a novel target of Wnt/β-catenin pathway, promotes growth of neuroendocrine tumor cells",
abstract = "Wnt/β-catenin signaling plays a pivotal role in regulating cell growth and differentiation by activation of the β-catenin/T-cell factor (TCF) complex and subsequent regulation of a set of target genes that have one or more TCF-binding elements (TBEs). Hyperactivation of this pathway has been implicated in numerous malignancies including human neuroendocrine tumors (NETs). Neurotensin (NT), an intestinal hormone, induces proliferation of several gastrointestinal (GI) cancers including cancers of the pancreas and colon. Here, we analyzed the human NT promoter in silico and found at least four consensus TBEs within the proximal promoter region. Using a combination of ChIP and luciferase reporter assays, we identified one TBE (located ∼900 bp proximal from the transcription start site) that was immunoprecipitated efficiently by TCF4-targeting antibody; mutation of this site attenuated the responsiveness to β-catenin. We also confirmed that the promoter activity and the mRNA and protein expression levels of NT were increased by various Wnt pathway activators and decreased by Wnt inhibitors in NET cell lines BON and QGP-1, which express and secrete NT. Similarly, the intracellular content and secretion of NT were induced by Wnt3a in these cells. Finally, inhibition of NT signaling suppressed cell proliferation and anchorage-independent growth and decreased expression levels of growth-related proteins in NET cells. Our results indicate that NT is a direct target of the Wnt/β-catenin pathway and may be a mediator for NET cell growth.",
keywords = "Neuroendocrine tumor cells, Neurotensin, Target gene, Wnt/β-catenin pathway",
author = "Kim, {Ji Tae} and Chunming Liu and Zaytseva, {Yekaterina Y.} and Weiss, {Heidi L.} and Courtney Townsend and Evers, {B. Mark}",
year = "2015",
month = "3",
day = "15",
doi = "10.1002/ijc.29123",
language = "English (US)",
volume = "136",
pages = "1475--1481",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "6",

}

TY - JOUR

T1 - Neurotensin, a novel target of Wnt/β-catenin pathway, promotes growth of neuroendocrine tumor cells

AU - Kim, Ji Tae

AU - Liu, Chunming

AU - Zaytseva, Yekaterina Y.

AU - Weiss, Heidi L.

AU - Townsend, Courtney

AU - Evers, B. Mark

PY - 2015/3/15

Y1 - 2015/3/15

N2 - Wnt/β-catenin signaling plays a pivotal role in regulating cell growth and differentiation by activation of the β-catenin/T-cell factor (TCF) complex and subsequent regulation of a set of target genes that have one or more TCF-binding elements (TBEs). Hyperactivation of this pathway has been implicated in numerous malignancies including human neuroendocrine tumors (NETs). Neurotensin (NT), an intestinal hormone, induces proliferation of several gastrointestinal (GI) cancers including cancers of the pancreas and colon. Here, we analyzed the human NT promoter in silico and found at least four consensus TBEs within the proximal promoter region. Using a combination of ChIP and luciferase reporter assays, we identified one TBE (located ∼900 bp proximal from the transcription start site) that was immunoprecipitated efficiently by TCF4-targeting antibody; mutation of this site attenuated the responsiveness to β-catenin. We also confirmed that the promoter activity and the mRNA and protein expression levels of NT were increased by various Wnt pathway activators and decreased by Wnt inhibitors in NET cell lines BON and QGP-1, which express and secrete NT. Similarly, the intracellular content and secretion of NT were induced by Wnt3a in these cells. Finally, inhibition of NT signaling suppressed cell proliferation and anchorage-independent growth and decreased expression levels of growth-related proteins in NET cells. Our results indicate that NT is a direct target of the Wnt/β-catenin pathway and may be a mediator for NET cell growth.

AB - Wnt/β-catenin signaling plays a pivotal role in regulating cell growth and differentiation by activation of the β-catenin/T-cell factor (TCF) complex and subsequent regulation of a set of target genes that have one or more TCF-binding elements (TBEs). Hyperactivation of this pathway has been implicated in numerous malignancies including human neuroendocrine tumors (NETs). Neurotensin (NT), an intestinal hormone, induces proliferation of several gastrointestinal (GI) cancers including cancers of the pancreas and colon. Here, we analyzed the human NT promoter in silico and found at least four consensus TBEs within the proximal promoter region. Using a combination of ChIP and luciferase reporter assays, we identified one TBE (located ∼900 bp proximal from the transcription start site) that was immunoprecipitated efficiently by TCF4-targeting antibody; mutation of this site attenuated the responsiveness to β-catenin. We also confirmed that the promoter activity and the mRNA and protein expression levels of NT were increased by various Wnt pathway activators and decreased by Wnt inhibitors in NET cell lines BON and QGP-1, which express and secrete NT. Similarly, the intracellular content and secretion of NT were induced by Wnt3a in these cells. Finally, inhibition of NT signaling suppressed cell proliferation and anchorage-independent growth and decreased expression levels of growth-related proteins in NET cells. Our results indicate that NT is a direct target of the Wnt/β-catenin pathway and may be a mediator for NET cell growth.

KW - Neuroendocrine tumor cells

KW - Neurotensin

KW - Target gene

KW - Wnt/β-catenin pathway

UR - http://www.scopus.com/inward/record.url?scp=84922236504&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922236504&partnerID=8YFLogxK

U2 - 10.1002/ijc.29123

DO - 10.1002/ijc.29123

M3 - Article

VL - 136

SP - 1475

EP - 1481

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 6

ER -