Nuclear factor-κB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer

Hiroshi Nakashima, Masafumi Nakamura, Hiroshi Yamaguchi, Naoki Yamanaka, Takashi Akiyoshi, Kenichiro Koga, Koji Yamaguchi, Masazumi Tsuneyoshi, Masao Tanaka, Mitsuo Katano

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-κB (NF-κB), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-κB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-κB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-κB by inflammatory stimuli, including interleukin-1β, tumor necrosis factor-α, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-κB. NF-κB-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-κB suppressed the enhanced cell proliferation. Our data suggest that NF-κB activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-κB activation in part through Shh overexpression.

Original languageEnglish
Pages (from-to)7041-7049
Number of pages9
JournalCancer Research
Volume66
Issue number14
DOIs
Publication statusPublished - Jul 15 2006

Fingerprint

Pancreatic Neoplasms
Cell Proliferation
Ligands
Chronic Pancreatitis
Interleukin-1
Embryonic Development
Lipopolysaccharides
Pancreas
Adenocarcinoma
Transcription Factors
Tumor Necrosis Factor-alpha
Messenger RNA
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Nuclear factor-κB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. / Nakashima, Hiroshi; Nakamura, Masafumi; Yamaguchi, Hiroshi; Yamanaka, Naoki; Akiyoshi, Takashi; Koga, Kenichiro; Yamaguchi, Koji; Tsuneyoshi, Masazumi; Tanaka, Masao; Katano, Mitsuo.

In: Cancer Research, Vol. 66, No. 14, 15.07.2006, p. 7041-7049.

Research output: Contribution to journalArticle

Nakashima, H, Nakamura, M, Yamaguchi, H, Yamanaka, N, Akiyoshi, T, Koga, K, Yamaguchi, K, Tsuneyoshi, M, Tanaka, M & Katano, M 2006, 'Nuclear factor-κB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer', Cancer Research, vol. 66, no. 14, pp. 7041-7049. https://doi.org/10.1158/0008-5472.CAN-05-4588
Nakashima, Hiroshi ; Nakamura, Masafumi ; Yamaguchi, Hiroshi ; Yamanaka, Naoki ; Akiyoshi, Takashi ; Koga, Kenichiro ; Yamaguchi, Koji ; Tsuneyoshi, Masazumi ; Tanaka, Masao ; Katano, Mitsuo. / Nuclear factor-κB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. In: Cancer Research. 2006 ; Vol. 66, No. 14. pp. 7041-7049.
@article{34f0ca755592487e9dd3c7d6e5b82628,
title = "Nuclear factor-κB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer",
abstract = "The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-κB (NF-κB), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-κB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-κB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-κB by inflammatory stimuli, including interleukin-1β, tumor necrosis factor-α, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-κB. NF-κB-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-κB suppressed the enhanced cell proliferation. Our data suggest that NF-κB activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-κB activation in part through Shh overexpression.",
author = "Hiroshi Nakashima and Masafumi Nakamura and Hiroshi Yamaguchi and Naoki Yamanaka and Takashi Akiyoshi and Kenichiro Koga and Koji Yamaguchi and Masazumi Tsuneyoshi and Masao Tanaka and Mitsuo Katano",
year = "2006",
month = "7",
day = "15",
doi = "10.1158/0008-5472.CAN-05-4588",
language = "English",
volume = "66",
pages = "7041--7049",
journal = "Cancer Research",
issn = "0008-5472",
number = "14",

}

TY - JOUR

T1 - Nuclear factor-κB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer

AU - Nakashima, Hiroshi

AU - Nakamura, Masafumi

AU - Yamaguchi, Hiroshi

AU - Yamanaka, Naoki

AU - Akiyoshi, Takashi

AU - Koga, Kenichiro

AU - Yamaguchi, Koji

AU - Tsuneyoshi, Masazumi

AU - Tanaka, Masao

AU - Katano, Mitsuo

PY - 2006/7/15

Y1 - 2006/7/15

N2 - The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-κB (NF-κB), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-κB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-κB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-κB by inflammatory stimuli, including interleukin-1β, tumor necrosis factor-α, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-κB. NF-κB-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-κB suppressed the enhanced cell proliferation. Our data suggest that NF-κB activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-κB activation in part through Shh overexpression.

AB - The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-κB (NF-κB), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-κB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-κB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-κB by inflammatory stimuli, including interleukin-1β, tumor necrosis factor-α, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-κB. NF-κB-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-κB suppressed the enhanced cell proliferation. Our data suggest that NF-κB activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-κB activation in part through Shh overexpression.

UR - http://www.scopus.com/inward/record.url?scp=33746888182&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746888182&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-05-4588

DO - 10.1158/0008-5472.CAN-05-4588

M3 - Article

C2 - 16849549

AN - SCOPUS:33746888182

VL - 66

SP - 7041

EP - 7049

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 14

ER -