Current Implications of microRNAs in Genome Stability and Stress Responses of Ovarian Cancer

Abstract

Genomic alterations and aberrant DNA damage signaling are hallmarks of ovarian cancer (OC), the leading cause of mortality among gynecological cancers worldwide. Owing to the lack of specific symptoms and late-stage diagnosis, survival chances of patients are significantly reduced. Poly (ADP-ribose) polymerase (PARP) inhibitors and replication stress response inhibitors present attractive therapeutic strategies for OC. Recent research has focused on ovarian cancer-associated microRNAs (miRNAs) that play significant regulatory roles in various cellular processes. While miRNAs have been shown to participate in regulation of tumorigenesis and drug responses through modulating the DNA damage response (DDR), little is known about their potential influence on sensitivity to chemotherapy. The main objective of this review is to summarize recent findings on the utility of miRNAs as cancer biomarkers, in particular, ovarian cancer, and their regulation of DDR or modified replication stress response proteins. We further discuss the suppressive and promotional effects of various miRNAs on ovarian cancer and their participation in cell cycle disturbance, response to DNA damage, and therapeutic functions in multiple cancer types, with particular focus on ovarian cancer. Improved understanding of the mechanisms by which miRNAs regulate drug resistance should facilitate the development of effective combination therapies for ovarian cancer.

Keywords: PARP; microRNA; ovarian cancer; replication stress; targeted therapy.

Figure 1

The main molecular steps involved in miRNA formation and organization.

Figure 2

The role of miRNAs as a regulator of DDR. DNA damage triggers the activation of the ATR/CHK1 pathway, which is responsible for substrates phosphorylation (i.e., H2AX, p53, and BRCA 1/2) to repair DNA damage. Single-strand DNA damage is identified and repaired by poly (ADP-ribose) polymerase (PARP) pathway activation, predominantly through base excision repair (BER). With continuous PARP inhibition, ssDNA breaks are converted to dsDNA breaks during DNA replication in which replication forks stall at the point of DNA damage. Over-expressed or down-regulated miRNAs may affect DDR by changing the expression of repair genes.

Figure 3

P53-induced miRNAs control cell cycle and cell survival in ovarian cancer. DNA damage stimulates ATR or DNA-PK kinases that activate TP53 to directly induce many kinds of miRNAs that repress cell-cycle regulators or allow to DNA repair. ATR transduces the DDR signal by phosphorylation of the checkpoint kinase CHK1, which results in cell cycle arrest and DNA repair. MiRNAs, e.g., miR-34a, a direct transcriptional target of TP53, participate in the regulation of TP53 activity. Activated TP53 translocates into the nucleus where it induces the transcription of several targets involved in cell cycle control, DNA repair, or apoptosis. DDR-related proteins that are MiRNAs recognizable are shown in blue box.

Figure 4

MiRNAs’ involvement in the DNA damage response in ovarian cancer. DNA synthesis inhibition or damage induces checkpoint responses. PARP and checkpoint proteins controlled by the ATR–CHK1 pathway prevent fork collapse, replication stress, and genome instability. DDR-related proteins that are MiRNAs recognizable are shown in blue box.

Figure 5

Schematic diagram representing several hallmarks of cancer contributing to pathogenesis of ovarian cancer. RNA markers involved in DDR signaling (PARP1, histone H2AX, P53, ATR, CHK1 regulation), cell cycle disturbance, metastasis, or epithelial–mesenchymal transmission are highlighted in blue.