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Authors:Fu, Yuanyuan
Contributors:Yu, Herbert (advisor)
Molecular Biosciences and Bioengineering (department)
Biomedical engineering
Molecular biology
show 4 morelong noncoding RNA
ovarian cancer
show less
Date Issued:2019
Publisher:University of Hawai'i at Manoa
Abstract:During the past decade, the development in genomics technologies has given us a new horizon of the RNA world, 98% of RNAs are not translated into proteins; numerous studies have shown aberrations within the noncoding genome drive important cancer phenotypes.
Ovarian cancer is the most lethal gynecological malignancy, accounting for more than 14,000 deaths every year in the United States. Currently, no reliable markers are available to predict ovarian cancer outcome and treatment response. Emerging evidence has suggested that long noncoding RNAs (lncRNAs) are involved in the development and progression of ovarian cancer, which may provide new prognostic and therapeutic opportunities.
This study is the first to identify four lncRNAs ASAP-IT1, FAM215A, TOPORS-AS1, and LINC00472 in association with clinical characteristics and survival outcomes of patients with epithelial ovarian cancer. LINC00472 and FAM215A differ significantly by tumor grade and disease stage; high expression of them is associated with low tumor grade and early disease stage. ASAP1-IT1 and TOPORS-AS1 have a similar trend in association with disease stage, but not tumor grade. High expression of ASAP1-IT1, FAM215A, TOPORS-AS1 is associated with favorable overall survival of ovarian cancer. Similar survival associations are also observed in an online database Kaplan-Meier Plotter. Meta-analysis results further confirm the relationship between TOPORS-AS1 and patient survival in large datasets, indicating that our findings are consistent across different studies and may promote the clinical utility of TOPORS-AS1 in evaluating patient prognosis with ovarian cancer.
Further functional in vitro studies show that TOPORS-AS1 markedly decreases ovarian cancer cell proliferation, migration, invasion and colony formation. However, the mechanism by which TOPORS-AS1 regulates ovarian cancer tumorigenesis remains elusive. Identifying the critical signaling pathway involved in TOPORS-AS1 overexpression is important for us to understand the mechanisms underlying ovarian cancer cellular division and growth.
The microarray results of this study show that TOPORS-AS1 suppresses ovarian cancer tumorigenesis through negatively regulating Wnt/b-catenin signaling, and this prediction has been confirmed by the signaling pathway components’ expression including b-catenin, LEF1, TCF1 and c-Myc, through comparing TOPORS-AS1 overexpressing cells with Mock transfected cells. b-catenin as the key factor of the signaling pathway and its downstream targets including LEF1, TCF1 and c-Myc, are all significantly suppressed by TOPORS-AS1 overexpression, and phosphorylated b-catenin expression is significantly increased by TOPORS-AS1 which leads to b-catenin degradation. Although no direct physical interaction has been found between TOPORS-AS1 and b-catenin, this study identifies that hnRNPA2B1 interacts with TOPORS-AS1 as well as b-catenin, which enhances TOPORS-AS1’s effects on b-catenin suppression. Vitamin D Receptor (VDR) has been experimentally confirmed binding to the promoter region of TOPORS-AS1 and upregulating TOPORS-AS1’s expression, and TOPORS-AS1 mediates VDR’s effect to decreases b-catenin expression and further suppress tumor progression.
In summary, lncRNAs TOPORS-AS1, ASAP1-IT1, and FAM215A, can serve as potential molecular biomarkers for ovarian cancer prognosis, and induction of TOPORS-AS1 by VDR or hnRNPA2V1 may provide preventive and therapeutic avenues for ovarian cancer.
Description:Ph.D. Thesis. Ph.D. Thesis. University of Hawaiʻi at Mānoa 2019
Pages/Duration:107 pages
Rights:All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections: Ph.D. - Molecular Biosciences and Bioengineering

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