Abstract
BackgroundEpithelial ovarian cancer (EOC) is one of the most malignant gynecological tumors worldwide. Deregulation of long non-coding RNAs (lncRNAs) has been implicated in various oncogenic processes in multiple cancers. In this study, we aim to identify and characterize clinically relevant lncRNA deregulation in EOC.MethodsLncRNAs, mRNAs and miRNAs were profiled using expression microarrays and validated using reverse transcription quantitative PCR in EOC cells and tissues. siRNAs targeting either HOXD-AS1 or PIK3R3 together with miR-186-5p inhibitors were used to modulate endogenous target expression in EOC cell lines in vitro. In vitro wound healing assay, trans-well assay, Western-blot assay,and Dual-luciferase reporter assay were used to explore the biological roles and molecular function underlying HOXD-AS1 in the EOC cells. Progression-free survival (PFS) and overall survival (OS) were statistically analyzed by Kaplan-Meier method test.ResultsHOXD-AS1 was found to be significantly over-expressed in EOC tumors. High HOXD-AS1 expression significantly correlated with poorer PFS and OS of EOC patients. Multivariate Cox proportional hazards modeling indicated that HOXD-AS1 was an independent risk predictor of EOC patients (HR = 1.92, p = 0.004). SiRNA inhibition of HOXD-AS1 reduced cell migration, invasion, and epithelial-mesenchymal transition (EMT) in EOC cells in vitro by preventing HOXD-AS1 directly binding to miR-186-5p, and resulting in down-regulating of PIK3R3. The novel HOXD-AS1/miR-186-5p/PIK3R3 pathway was clinically relevant as we observed a significantly inverse correlation between HOXD-AS1/miR-186-5p and between miR-186-5p/PIK3R3 in an independent cohort of 200 EOC tissues.ConclusionsHOXD-AS1/miR-186-5p/PIK3R3 is a novel pathway to promote cell migration, invasion, and EMT in EOC.
Highlights
Epithelial ovarian cancer (EOC) is one of the most malignant gynecological tumors worldwide
We validated the robustness of the array data by randomly choosing ten Long noncoding RNAs (lncRNA) from these 288 differentially expressed lncRNAs in an independent cohort of 50 samples comprising of 36 EOC tissues and 14 normal ovary tissues
All ten lncRNAs showed differential expression between EOC and normal ovary tissues which was in concordance with what we observed in the microarrays
Summary
Epithelial ovarian cancer (EOC) is one of the most malignant gynecological tumors worldwide. XIST, which is a lncRNA over-expressed in colorectal cancer tissues and cells, can promote invasion, proliferation, and EMT progress through XIST/miR200b-3p/ZEB1 pathway [17]. Another example is PVT1, a highly expressed lncRNA in prostate cancer cells that can co-regulate Twist with miR-186 and promote tumor invasion, migration, and the progress of EMT [18]. This lncRNA/miRNA/mRNA pathway has been proposed as a new model by which lncRNAs regulate target gene expression through miRNA response elements [19]. Salmena et al have termed this phenomenon as the competing endogenous RNA (ceRNA) theory [20]
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