Targeting Long Noncoding RNA UCA1 for Ovarian Cancer Therapy
Abstract
Ovarian cancer remains the most fatal of the gynecological cancers. This is primarily due to the asymptomatic nature of the disease that often leads to late diagnosis and the lack of an effective targeted therapy. Therefore, better understanding of the mechanisms underlying ovarian cancer genesis and progression is critically needed to develop effective diagnostic and therapeutic strategies. The overarching goal of this project is to improve the current understanding of the mechanisms underlying ovarian cancer genesis and progression so that more effective diagnostic and therapeutic strategies can be developed. Towards this goal, we investigated whether any new therapeutic signaling targets can be identified in ovarian cancer that can improve treatment efficiency and increase the overall survival of the ovarian cancer patients. Recent studies have shown that a family of long non-coding RNAs (lncRNA), which are being referred as the "Genomic Dark Matter," are emerging as critical molecules involved in multiple cellular events including tumorigenesis and tumor progression. A recent study has indicated that 68% of the human genome encodes such non-protein coding RNAs. While the molecular mechanism of action is known only for a handful of these lncRNAs, it has been elegantly demonstrated that the lncRNAs have multiple, but non-mutually exclusive, functions in different cellular compartments and physiological contexts. Considering the fact that ovarian cancer remains the most fatal of the gynecological cancers, we sought to investigate whether lncRNAs play a role in ovarian cancer genesis and progression. Using cell-based as well as xenograft tumor mouse models, along with the interrogative analysis of human ovarian cancer tissue samples, we propose to further characterize the role of this lncRNA in regulating ovarian cancer growth and therapy resistance and assess its role as a therapeutic target. In this proposal, we provide extensive preliminary data that can substantiate the proposed objectives of the application. Our preliminary studies using ovarian cancer cell lines, as well as patient-derived ovarian cancer cells and tissues, show a strong association between the expression of urothelial carcinoma associated 1 (UCA1), a long intergenic lncRNA and ovarian cancer pathobiology including cell proliferation, invasive-migration, epithelial-mesenchymal transition, and drug resistance. Furthermore, a tissue microarray analysis of 126 ovarian cancer patients shows that UCA1 is overexpressed in ovarian cancer tissues and increased expression of UCA1 can be correlated with poor overall survival in ovarian cancer patients. Our initial functional characterization studies with UCA1 using RNA-immunoprecipitation and cross-linking immunoprecipitation assays have indicated that UCA1 physically interacts with the polycomb group of proteins that are involved in epigenetic control of gene expression. Based on these findings, we hypothesize that UCA1 represses tumor safeguard mechanisms of the cells to promote tumor progression; and inhibition of UCA1 can suppress tumor growth, therapy resistance, and disease recurrence. This integrated hypothesis will be tested under three specific aims: Aim 1 will investigate the mechanisms through which the expression of UCA1 is elevated in ovarian cancer; Aim 2 will investigate the mechanism by which UCA1 regulates oncogenic signaling; and, Aim 3 will test the efficacy of targeting UCA1 alone or in combination with cisplatin to inhibit tumor growth and therapy resistance. It is anticipated that the outcome of these studies will facilitate the development of novel diagnostic, prognostic, or therapeutic targets for ovarian cancer. More importantly, the proposed studies will evaluate whether targeting this lncRNA could play a synergistic role with the existing therapies. Thus, our studies proposed here collectively address "Treatment Resistance" as well as "Novel Therapies and Associa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810066
Entities
People
- Danny Dhanasekaran
Organizations
- United States Army
- University of Oklahoma Health Sciences Center