Gli1 contributes to the invasiveness of pancreatic cancer through matrix metalloproteinase-9 activation.
The hedgehog (Hh) signaling pathway has been reported to be associated with the growth of pancreatic cancer, but its role in the invasive phenotype is poorly understood. Therefore, we investigated the role of the Hh pathway in pancreatic cancer cell invasiveness using a Matrigel invasion assay. Blockade of the Hh pathway by cyclopamine inhibited pancreatic cancer cell invasion in association with a decreased expression of matrix metalloproteinase (MMP)-9. By contrast, activation of the Hh pathway by the addition of exogenous Sonic hedgehog increased cell invasion and MMP-9 expression. Stable transfection of pancreatic cancer cells with Gli1 increased their invasiveness, which was associated with activation of MMP-9. We also showed that inhibition of MMP-9 by small interfering RNA blocked the increased invasiveness of Gli1-transfected cells. Furthermore, inhibition of Gli1 by small interfering RNA suppressed the invasiveness and MMP-9 expression of pancreatic cancer cells. Taken together, these findings suggest that members of the Hh pathway, especially Gli1, play an important role in the invasiveness of pancreatic cancer cells through the regulation of MMP-9 expression.
Nagai
Shuntaro
S
Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Nakamura
Masafumi
M
Yanai
Kosuke
K
Wada
Junji
J
Akiyoshi
Takashi
T
Nakashima
Hiroshi
H
Ohuchida
Kenoki
K
Sato
Norihiro
N
Tanaka
Masao
M
Katano
Mitsuo
M
D045744:Cell Line, Tumor; D053823:Hedgehog Proteins / Q000502:physiology; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D053583:Interleukin-1beta; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9