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Suppression of Progression and Metastasis of Established Colon Tumors in Mice by Intravenous Delivery of Short Interfering RNA Targeting KITENIN, a Metastasis-Enhancing Protein

 Ji Hee Lee  ;  Eun Song Cho  ;  Kyung Keun Kim  ;  Kyu Youn Ahn  ;  Nack Sung Kim  ;  Hyun Kook  ;  Ik Joo Chung  ;  Dhong Hyo Kho  ;  Young-Woo Seo  ;  Mi-Young Kim 
 CANCER RESEARCH, Vol.65(19) : 8993-9003, 2005 
Journal Title
Issue Date
Adenocarcinoma/genetics ; Adenocarcinoma/immunology ; Adenocarcinoma/pathology ; Adenocarcinoma/therapy* ; Animals ; Antigens, Neoplasm ; Biomarkers, Tumor ; Carrier Proteins/antagonists & inhibitors* ; Carrier Proteins/biosynthesis ; Carrier Proteins/genetics ; Carrier Proteins/immunology ; Carrier Proteins/metabolism ; Cell Line, Tumor ; Coculture Techniques ; Colonic Neoplasms/genetics ; Colonic Neoplasms/immunology ; Colonic Neoplasms/pathology ; Colonic Neoplasms/therapy* ; DNA, Antisense/genetics ; Glycoproteins/biosynthesis ; Glycoproteins/genetics ; Glycoproteins/metabolism ; Humans ; Injections, Intravenous ; Interleukin-1/metabolism ; Interleukin-6/metabolism ; Macrophages/metabolism ; Membrane Proteins/antagonists & inhibitors* ; Membrane Proteins/biosynthesis ; Membrane Proteins/genetics ; Membrane Proteins/immunology ; Mice ; Mice, Inbred BALB C ; Protein Kinase C/antagonists & inhibitors ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Small Interfering/administration & dosage* ; RNA, Small Interfering/genetics* ; RNA, Small Interfering/immunology ; Transfection ; Xenograft Model Antitumor Assays
KITENIN promotes invasion of mouse colon adenocarcinoma (CT-26) cells in vivo. Here, we studied the effects of in vivo KITENIN ablation on established tumors by using pSUPER vectors (pSUPER-KITENIN) producing short interfering RNA (siRNA). When pSUPER-KITENIN was given weekly or semiweekly for 1 month into tail vein of syngeneic mice that have established colon tumors, tumor size regressed markedly and metastases were inhibited. In mice injected with pSUPER-KITENIN, serum interleukin-2 (IL-2) and IFN-γ increased and CD4+ and CD8+ T cells infiltrated in the regressed tumor tissues. These effects, observed beginning 2 days after i.v. injection, imply that immune response is involved in the antitumor action of pSUPER-KITENIN. Using a yeast two-hybrid assay, we identified two KITENIN-interacting proteins for the possible mediators of these actions: 90K protein, a known immune modulatory glycoprotein, and protein kinase C inhibitor (PKCI). 90K was increased in the culture medium from CT-26/antisense KITENIN/90K cells. Double culture of accessory cells with CT-26/antisense KITENIN/90K cells revealed increased secretion of IL-1 and IL-6. Overexpression of 90K in CT-26/antisense KITENIN cells further delayed tumor growth compared with that of CT-26/antisense KITENIN cells. Actin arrangement was distorted in CT-26/antisense KITENIN and CT-26/antisense PKCI cells, whereas overexpression of PKCI resulted in increased invasiveness to fibronectin. Thus, antitumor effects of KITENIN siRNA derives from both the generation of a tumor-specific immune response in vivo through increased 90K secretion from tumor cells and the suppression of tumor invasion in which PKCI is related to increased invasiveness. Moreover, siRNA targeting of KITENIN can function as a chemotherapeutic strategy against colon cancer.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Mi Young(김미영)
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