Claudin-3 gene silencing with siRNA suppresses ovarian tumor growth and metastasis.
Claudin-3 (CLDN3) is a tight junction protein that is overexpressed in 90% of ovarian tumors. Previous in vitro studies have indicated that CLDN3 overexpression promotes the migration, invasion, and survival of ovarian cancer cells. Here, we investigated the efficacy of lipidoid-formulated CLDN3 siRNA in 3 different ovarian cancer models. Intratumoral injection of lipidoid/CLDN3 siRNA into OVCAR-3 xenografts resulted in dramatic silencing of CLDN3, significant reduction in cell proliferation, reduction in tumor growth, and a significant increase in the number of apoptotic cells. Intraperitoneal injection of lipidoid-formulated CLDN3 siRNA resulted in a substantial reduction in tumor burden in MISIIR/TAg transgenic mice and mice bearing tumors derived from mouse ovarian surface epithelial cells. Ascites development was reduced in CLDN3 siRNA-treated mice, suggesting the treatment effectively suppressed metastasis. Toxicity was not observed after multiple i.p. injections. Importantly, treatment of mice with nonimmunostimulatory 2'-OMe modified CLDN3 siRNA was as effective in suppressing tumor growth as unmodifed siRNA. These results suggest that lipidoid-formulated CLDN3 siRNA has potential as a therapeutic for ovarian cancer.
Huang
Yu-Hung
YH
Lankenau Institute for Medical Research, 100 E Lancaster Avenue, Wynnewood, PA 19096-3450, USA.
Bao
Yunhua
Y
Peng
Weidan
W
Goldberg
Michael
M
Love
Kevin
K
Bumcrot
David A
DA
Cole
Geoffrey
G
Langer
Robert
R
Anderson
Daniel G
DG
Sawicki
Janet A
JA
D000818:Animals; D045744:Cell Line, Tumor; D062465:Claudin-3; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
C568122:CLDN3 protein, human; D062465:Claudin-3; C568123:Cldn3 protein, mouse; D008565:Membrane Proteins; D034741:RNA, Small Interfering