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Review
. 2022 Jun 16;23(12):6702.
doi: 10.3390/ijms23126702.

ROS and miRNA Dysregulation in Ovarian Cancer Development, Angiogenesis and Therapeutic Resistance

David C Stieg  1 , Yifang Wang  2 , Ling-Zhi Liu  1 , Bing-Hua Jiang  2
Affiliations
Review

ROS and miRNA Dysregulation in Ovarian Cancer Development, Angiogenesis and Therapeutic Resistance

David C Stieg et al. Int J Mol Sci. .

Abstract

The diverse repertoires of cellular mechanisms that progress certain cancer types are being uncovered by recent research and leading to more effective treatment options. Ovarian cancer (OC) is among the most difficult cancers to treat. OC has limited treatment options, especially for patients diagnosed with late-stage OC. The dysregulation of miRNAs in OC plays a significant role in tumorigenesis through the alteration of a multitude of molecular processes. The development of OC can also be due to the utilization of endogenously derived reactive oxygen species (ROS) by activating signaling pathways such as PI3K/AKT and MAPK. Both miRNAs and ROS are involved in regulating OC angiogenesis through mediating multiple angiogenic factors such as hypoxia-induced factor (HIF-1) and vascular endothelial growth factor (VEGF). The NAPDH oxidase subunit NOX4 plays an important role in inducing endogenous ROS production in OC. This review will discuss several important miRNAs, NOX4, and ROS, which contribute to therapeutic resistance in OC, highlighting the effective therapeutic potential of OC through these mechanisms.

Keywords: HER3; HIF1-α; NOX4; ROS; VEGF; angiogenesis; miRNA dysregulation; ovarian cancer; therapeutic resistance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The roles of miRNA dysfunction in OC development. As described in the text, the miRNAs shown above are dysregulated in OC that contribute to angiogenesis, cell proliferation, and therapeutic resistance. The dysregulation of each miRNA is denoted by an up arrow (upregulation) or a down arrow(downregulation). The regulation of proteins affected by the dysregulation miRNAs is denoted in the same manner.
Figure 2
Figure 2
NOX4-driven pathways of OC tumor progression, angiogenesis and therapeutic resistance. The overexpression of NOX4 in OC results in an increase in intracellular ROS production. Increased ROS leads to an increase in HIF1-A through activating PI3K and AKT signaling. HIF1-α then activates the critical angiogenic factor, VEGF. Increased ROS also activates NF-κB and TGF-β1 signaling, which lead to the direct upregulation of NOX4. The increase in NOX4 contributes, in a positive-feedback manner, to increased ROS production. NOX4 also activates the expression of HER3, contributing to therapeutic resistance in OC tumors.
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