miRNA Influences in NRF2 Pathway Interactions within Cancer Models

Abstract

The NRF2 transcription factor (nuclear factor-erythroid 2 p45-related factor 2) has been identified as a key molecular player in orchestrating adaptive cellular interactions following a wide spectrum of cellular stress conditions that could be either extracellular or intracellular. Dysregulation of the NRF2 system is implicated in various disease states, including inflammatory conditions. The NRF2 transcription factor is also known to permit cross talk with several other essential cellular signaling pathways. Recent literature has also elucidated the potential influences of miRNA activity over modulations of the NRF2 signalling network. Consequently, further delving into the knowledge regarding the extent of miRNA-induced epigenetic gene regulatory control on key elements of the NRF2 signalling pathway and its cross talk, particularly within the context of cancer models, can prove to be of high clinical importance. This is so since such miRNAs, once identified and validated, can be potentially exploited as novel drug targets for emerging translational medicine-based therapies.

Figure 1

Known regulatory mechanisms of NRF2, highlighting miRNA-mediated influences. Important regulatory pathways include the inhibition of the NF-κB proinflammatory and ROS pathways. Eight miRNAs have also been identified as direct modulators of NRF2 expression at the transcriptomic level.

Figure 2

Overview of ROS-mediated NRF2 activities. A feedback mechanism exists, which provides a fine balance between free circulating cytoplasmic NRF2 and nuclear ARE motif-bound NRF2, with miRNAs such as miR-29-b1 and miR-144 providing direct regulation of NRF2 expression within the cytoplasm.

Figure 3

Overview of carcinogenesis and NRF2 responses. Tumour progression is recognized to induce dysregulated miRNA expression, resulting in exacerbated NRF2 activity. Such downstream effects include reduced apoptotic mechanism induction and exacerbation of chemoresistance properties by the tumour, therefore thwarting any conventional cancer therapeutic success.