Back to the Future: Rethinking the Great Potential of lncRNAS for Optimizing Chemotherapeutic Response in Ovarian Cancer

Abstract

Ovarian cancer (OC) is one of the most fatal cancers in women worldwide. Currently, platinum- and taxane-based chemotherapy is the mainstay for the treatment of OC. Yet, the emergence of chemoresistance results in therapeutic failure and significant relapse despite a consistent rate of primary response. Emerging evidence substantiates the potential role of lncRNAs in determining the response to standard chemotherapy in OC. The objective of this narrative review is to provide an integrated, synthesized overview of the current state of knowledge regarding the role of lncRNAs in the emergence of resistance to platinum- and taxane-based chemotherapy in OC. In addition, we sought to develop conceptual frameworks for harnessing the therapeutic potential of lncRNAs in strategies aimed at enhancing the chemotherapy response of OC. Furthermore, we offered significant new perspectives and insights on the interplay between lncRNAs and the molecular circuitries implicated in chemoresistance to determine their impacts on therapeutic response. Although this review summarizes robust data concerning the involvement of lncRNAs in the emergence of acquired resistance to platinum- and taxane-based chemotherapy in OC, effective approaches for translating these lncRNAs into clinical practice warrant further investigation.

Keywords: chemotherapy; dysregulated expression; long non-coding RNAs; mechanisms of resistance; ovarian cancer.

Figure 1

Classification of long non-coding RNAs (lncRNAs) based on their genomic location. Intergenic lncRNA is located between two protein-coding genes. Intronic lncRNA lies entirely within the intron of a protein-coding gene. Sense lncRNA is transcribed from the same strand and in the same direction as the nearby protein-coding genes. Antisense lncRNA is transcribed from an opposite strand. Bidirectional lncRNA is located within 1 kb of the promoter region of a protein-coding gene but is transcribed from an opposite strand.

Figure 2

General biological functions of lncRNAs. lncRNA biological functions are generally categorized into four main archetypes of molecular mechanisms, including (A) signals, (B) guides, (C) decoys, and (D) scaffolds. In addition, lncRNAs exert diverse regulatory functions originating from these archetypes such as regulation of; (E) chromatin remodeling via modulating recruitment of epigenetic factors, (F) transcription through controlling transcription factors or RNA polymerase 2 (RNA pol II), (G) protein translation, (H) alternative splicing and other post-transcriptional modifications, (I) protein ubiquitination and other post-translational modifications (PTMs), (J) miRNA-induced gene silencing via sponging miRNA as a part of the RNA-induced silencing complex (RISC), and (K) mRNA stability by modulating mRNA-degrading enzymes.

Figure 3

Molecular mechanisms of lncRNAs involved in platinum resistance. The lncRNA ZFAS1 enhances cisplatin resistance through regulating the miR-150-5p/SP1/copper transporter 1 (CTR1) axis. Nuclear-enriched abundant transcript 1 (NEAT1) ameliorates platinum resistance via upregulating epigallocatechin-3-gallate (EGCG)-induced CTR1 expression. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and LINC00152 promote cisplatin resistance through activating MRP1. Homeobox transcript antisense RNA (HOTAIR) enhances platinum resistance via activating autophagy and Wnt/β catenin-induced epithelial–mesenchymal transition (EMT). The lncRNA H19 induces platinum resistance via enhancing the expression of nuclear factor erythroid 2 (NRF2) and glutathione (GSH), thereby preventing reactive oxygen species (ROS)-induced cytotoxicity. Moreover, H19 promotes platinum resistance by activating transcription factors involved in EMT.

Figure 4

lncRNAs regulate platinum resistance via modulating DNA-damage-induced apoptosis. Growth arrest-specific transcript 5 (GAS5) mitigates cisplatin resistance via inhibiting PARP1-induced DNA repair. Colon cancer-associated transcript 1 (CCAT1) promotes platinum resistance through sponging miR-454, thereby activating survivin and inhibiting apoptosis. HOTAIR exacerbates platinum resistance through activating NF-κB, leading to increased expression of survival genes. lncRNAs promoter of CDKN1A antisense DNA damage activated RNA (PANDAR), E2F-mediated proliferation enhancing lncRNA (EPEL), and HOTAIR induce platinum resistance via inhibiting p53-induced apoptosis, while plasmacytoma variant translocation 1 (PVT1) inhibits platinum resistance via promoting p53-induced apoptosis.

Figure 5

Major lncRNAs involved in taxane resistance. LINC01118 and urothelial carcinoma associated 1 (UCA1) promote taxane resistance via activating ATP-binding cassette (ABC) family and drug efflux. Linc00312 circumvents taxane resistance through suppressing Bcl2 and inducing apoptosis. Succinate dehydrogenase complex, subunit A, flavoprotein pseudogene 1 (SDHAP1) promotes taxane resistance via sponging miR-4465, consequently enhancing EIF4G2 and initiating protein translation. FER1L4 mitigates taxane resistance by suppressing the mitogen-activated protein kinase (MAPK) pathway. UCA1 promotes taxane resistance by regulating the miR-654-5p/SIK2 axis. NEAT1 promotes taxane resistance via sponging miR-194, thereby activating ZEB1 and EMT. KB-1471A8.2 ameliorates taxane resistance by blocking CDK4 and S-phase entry.