Abstract
Growing evidence shows that cancer cells use mRNA-binding proteins and miRNAs to posttranscriptionally regulate signaling pathways to adapt to harsh tumor microenvironments. In ovarian cancer, cytoplasmic accumulation of mRNA-binding protein HuR (ELAVL1) is associated with poor prognosis. In this study, we observed high HuR expression in ovarian cancer cells compared with ovarian primary cells, providing a rationale for targeting HuR. RNAi-mediated silencing of HuR in ovarian cancer cells significantly decreased cell proliferation and anchorage-independent growth, and impaired migration and invasion. In addition, HuR-depleted human ovarian xenografts were smaller than control tumors. A biodistribution study showed effective tumor-targeting by a novel Cy3-labeled folic acid (FA)-derivatized DNA dendrimer nanocarrier (3DNA). We combined siRNAs against HuR with FA-3DNA and found that systemic administration of the resultant FA-3DNA-siHuR conjugates to ovarian tumor-bearing mice suppressed tumor growth and ascites development, significantly prolonging lifespan. NanoString gene expression analysis identified multiple HuR-regulated genes that function in many essential cellular and molecular pathways, an attractive feature of candidate therapeutic targets. Taken together, these results are the first to demonstrate the versatility of the 3DNA nanocarrier for in vivo-targeted delivery of a cancer therapeutic and support further preclinical investigation of this system adapted to siHuR-targeted therapy for ovarian cancer.
Highlights
Ovarian cancer is the second most common gynecologic cancer in the United States
HuR accumulation correlates with poor disease progression, HuR expression is high across different grades of ovarian cancer, and strong nuclear HuR staining is often found in high-grade ovarian carcinoma [13, 17]
In a Western blot analysis, we found that all ovarian cancer cells tested (A2780, OVCAR3, OVCAR5, and OVCA420) express higher levels of HuR (2–6 fold) compared with ovarian primary cells (HIO80 and HIO120; Fig. 1A)
Summary
Ovarian cancer is the second most common gynecologic cancer in the United States. It has been perceived as a silent killer due to its asymptomatic nature during the early stages of disease progression. Ovarian cancers are classified into a number of different subtypes depending on cellular origin and histologic characteristics, epithelial ovarian cancer being by far the most common type [1]. The current clinical regimen for treating ovarian carcinoma is typically surgical debulking followed by chemotherapy with paclitaxel and a platinum-based therapy (cisplatin or carboplatin). 80% of patients receiving this treatment have an initial favorable response, most tumors will eventually relapse accompanied by the development of chemoresistance.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
