Claudin-3 gene silencing with siRNA suppresses ovarian tumor growth and metastasis.

Abstract

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.

• Authors: Yu-Hung Huang, Yunhua Bao, Weidan Peng, Michael Goldberg, Kevin Love, David A Bumcrot, Geoffrey Cole, Robert Langer, Daniel G Anderson, Janet A Sawicki
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 9 Pg. 3426-30 (Mar 03 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19208807 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CLDN3 protein, human
• Claudin-3
• Cldn3 protein, mouse
• Membrane Proteins
• RNA, Small Interfering

Topics

• Animals
• Cell Line, Tumor
• Claudin-3
• Disease Models, Animal
• Disease Progression
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Metastasis (pathology)
• Ovarian Neoplasms (genetics, metabolism, pathology)
• RNA, Small Interfering (genetics)
• Xenograft Model Antitumor Assays