Dysregulated Expression of Long Noncoding RNAs in Ovarian Cancer

Abstract

Ovarian cancer is the leading cause of death among women with gynecologic malignancies. The development and progression of ovarian cancer are complex and a multiple-step process. New biomarker molecules for diagnostic and prognostic are essential for novel therapeutic targets and to extend the survival time of patients with ovarian cancer. Long noncoding RNAs (lncRNAs) are non-protein-coding transcripts longer than 200 nucleotides that have recently been found as key regulators of various biological processes and to be involved in the development and progression of many diseases including cancers. In this review, we summarized the expression pattern of several dysregulated lncRNAs (HOTAIR, H19, XIST, and HOST2) and the functional molecular mechanism of these lncRNAs on the initiation and progression of ovarian cancer. The lncRNAs as biomarkers may be used for current and future clinical diagnosis, therapeutics, and prognosis.

FIGURE 1

A schematic diagram of HOST2 enhances the endogenous expression of metastasis-promoting genes that are targeted by let-7b. A, Down-regulation of HOST2 may increase let-7b activity, which would inhibit expression of its target genes (HMGA2, c-myc, Dicer, and Imp3). B, High regulation of HOST2 binds to more let-7b and increases expression of its target genes (HMGA2, c-myc, Dicer, and Imp3).

FIGURE 2

A schematic diagram of the mechanisms of HOTAIR. HOTAIR when combined with PRC2 (composed of EZH2, SUZ12, and EED) can trimethylate histone H3 at lysine 27 (H3K27me3) and inhibit HOXD gene expression.

FIGURE 3

A schematic diagram of epigenetic mechanisms of H19 repression mediated by H1.3 Histone H1.3 overexpression leads to increased occupancy of H1.3 at the H19 regulator region encompassing the ICR, concomitant with increased DNA methylation and reduced occupancy of the insulator protein CTCF at the ICR, which can inhibit the expression of H19.

FIGURE 4

Dysregulation and functional roles of lncRNAs in OC. A, HOST2 could increase cell metastasis, invasion, and proliferation via binding to let-7b and inhibiting the function of let-7b, and then increase expression of its target genes (HMGA2, c-myc, Dicer, and Imp3). B, HOTAIR represented a prognostic marker and increased cell metastasis and invasion by regulating EMT-related genes; HOTAIR promoted SOC cell proliferation and decreased cell apoptosis by regulating certain cell cycle– and apoptotic-related genes (cyclin E, BCL-2, caspase-9, caspase-3, and BRCA1). C, H19 increased cell proliferation. D, LSINCT5 increased cell proliferation. E, MEG3 promoted cell proliferation and decreased cell apoptosis via p53. F, PVT1 inhibited cell apoptosis and increased cell proliferation and carboplatin resistance in OC by knockdown the expression of TGF-β1, p-smad4, and Caspase-3. G, BC200 inhibited OC cell proliferation and increased the sensitivity of OC cells to carboplatin. H, XIST could inhibit OC cell resistance to paclitaxel via reactivating the X-specific resistance gene. I, UCA1 promoted invasion and metastasis by up-regulating MMP2 and MMP9 expression in OC cells; UCA1 represented a prognostic marker and enhanced EOC metastasis through the UCA1-miR-485-5p-MMP14 axis.