Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer.
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-kappaB (NF-kappaB), 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-kappaB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-kappaB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-kappaB by inflammatory stimuli, including interleukin-1beta, tumor necrosis factor-alpha, 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-kappaB. NF-kappaB-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-kappaB suppressed the enhanced cell proliferation. Our data suggest that NF-kappaB activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-kappaB activation in part through Shh overexpression.
Nakashima
Hiroshi
H
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Nakamura
Masafumi
M
Yamaguchi
Hiroshi
H
Yamanaka
Naoki
N
Akiyoshi
Takashi
T
Koga
Kenichiro
K
Yamaguchi
Koji
K
Tsuneyoshi
Masazumi
M
Tanaka
Masao
M
Katano
Mitsuo
M
D000818:Animals; D019556:COS Cells; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D053823:Hedgehog Proteins; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000378:metabolism; D015854:Up-Regulation
D053823:Hedgehog Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; C509239:SHH protein, human; D015534:Trans-Activators; D051996:Transcription Factor RelA