Id1/Id3 knockdown inhibits metastatic potential of pancreatic cancer.
BACKGROUND
The Id (inhibitor of DNA binding/differentiation) proteins belong to the helix-loop-helix transcriptional regulatory factors, and play important roles in tumor development. Previously, we and others have shown that targeting Id in tumor cells could have important clinical implications. In the present study, we aimed to evaluate the effects of Id inhibition in human pancreatic cancer cells.


METHODS
Id1 and Id3 were stably double-knockdown in human pancreatic cancer cell line MIA-Paca2 by means of RNA interference. Expression of Id and integrins were analyzed by flow-cytometry. Cell proliferation was evaluated by MTS assay. Migration was measured by wound closure assay. Adhesion assay was performed to evaluate binding capacity for different extracellular matrix proteins. Finally, in vivo properties of tumor cells were observed in a mouse model of peritoneal metastasis.


RESULTS
Id1/Id3 double-knockdown resulted in decreased ability of pancreatic cancer cells to proliferate and migrate. In addition, Id1/Id3 double-knockdown caused decreased expression of integrins alpha3, alpha6, and beta1, and consequently reduced adhesion of tumor cells to laminin. Finally, peritoneal metastases of Id1/Id3 double-knockdown tumor cells were significantly reduced.


CONCLUSIONS
We concluded that the Id proteins play a pivotal role in the development of peritoneal metastasis of pancreatic cancer, and consequently, their targeting would be a novel strategy for the prevention and treatment of pancreatic cancer.
Shuno
Yasutaka
Y
Department of Surgical Oncology, University of Tokyo, Tokyo, Japan. shuu@tkg.att.ne.jp
Tsuno
Nelson H
NH
Okaji
Yurai
Y
Tsuchiya
Takeshi
T
Sakurai
Daisuke
D
Nishikawa
Takeshi
T
Yoshikawa
Naoyuki
N
Sasaki
Kazuhito
K
Hongo
Kumiko
K
Tsurita
Giichiro
G
Sunami
Eiji
E
Kitayama
Joji
J
Tokunaga
Katsushi
K
Takahashi
Koki
K
Nagawa
Hirokazu
H
D002277:Carcinoma / Q000378:metabolism* / Q000628:therapy; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000628:therapy; D034622:RNA Interference
D016326:Extracellular Matrix Proteins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D051796:Inhibitor of Differentiation Proteins; D016023:Integrins; D009363:Neoplasm Proteins; C075640:ID3 protein, human