microRNAs Tune Oxidative Stress in Cancer Therapeutic Tolerance and Resistance

Abstract

Relapsed disease following first-line therapy remains one of the central problems in cancer management, including chemotherapy, radiotherapy, growth factor receptor-based targeted therapy, and immune checkpoint-based immunotherapy. Cancer cells develop therapeutic resistance through both intrinsic and extrinsic mechanisms including cellular heterogeneity, drug tolerance, bypassing alternative signaling pathways, as well as the acquisition of new genetic mutations. Reactive oxygen species (ROSs) are byproducts originated from cellular oxidative metabolism. Recent discoveries have shown that a disabled antioxidant program leads to therapeutic resistance in several types of cancers. ROSs are finely tuned by dysregulated microRNAs, and vice versa. However, mechanisms of a crosstalk between ROSs and microRNAs in regulating therapeutic resistance are not clear. Here, we summarize how the microRNA–ROS network modulates cancer therapeutic tolerance and resistance and direct new vulnerable targets against drug tolerance and resistance for future applications.

Crosstalk between MicroRNA and Oxidative Stress in Physiology and Pathology

“…Furthermore, Yamakawa et al [12] address the subject of the possible development of Clinical Trials of Nucleic Acid Medicine, and their delivery systems for Pancreatic Cancer. Of note, among the above quoted contributors, Zhang [9] points out the opportunity of Large-Scale Screenings and Artificial Intelligence-based technology to optimize the therapeutic approach, that is, in accordance with our considerations about complexity in the conclusive remarks. Additionally, a very interesting overview comes from the paper by Marí-Alexandre et al [13], who analyze the role of oxidative stress and miRNA in the pathophysiology of endometriosis and its possible evolution towards Ovarian Cancers: with their paper, they also provide a valuable educational contribution to this subject.…”

“…A large contribution has been provided on cancer research. Cosentino et al [7], dealing with Breast Cancer; Huang et al [8] with Human Hepatocellular Aarcinoma; Zhang [9] for therapeutic tolerance and resistance as a general subject; and Lin. [10] and Babu and Tay [11] on the overall ROS-miRNA relationship domain.…”

Non-Coding RNAs in Lung Tumor Initiation and Progression

“…Homogenous KRAS G12D mutant, a common mutation causing dysregulation of the MAPK pathway, has been reported to favor glucose fueled TCA cycling due to glucose metabolic reprogramming and reactive oxygen species (ROS) management, leading to increased malignancy [255]. The interplay between miRNA and ROS in cancer treatment response has been discussed in recent reviews [256,257]. Non-coding RNAs such as miR-21 and miR-30c have shown upregulation with KRAS G12D overexpression, which as a result enhance regulation of Ras downstream pathways [207].…”

miR129‑1 regulates protein phosphatase 1D protein expression under hypoxic conditions in non‑small cell lung cancer cells harboring a TP53 mutation

“…Given that RBM38 regulates cellular responses to oxidative stress by regulating translation of hypoxia-inducible factor 1α ( HIF1A ) ( 18 ), and HIF1α protein forms a complex with mutant p53 protein and induces transcription of extracellular matrix components promoting migration and invasion ( 19 ), it may be possible that the PPM1D-RBM38-mutant p53 axis is regulated differently in normoxic and hypoxic conditions. Indeed, microRNAs (miRNAs), a class of small non-coding RNA ~22 nucleotides long, have been shown to differentially regulate cellular response under hypoxic and normoxic conditions ( 20 ). miR-129-1-3p and miR-129-1-5p have been shown to function as tumor suppressors in colon, gastric, bladder, and esophageal cancer ( 21 – 24 ).…”