Focus on the Progress of miRNA Research Made by Scientists in Recent Years (Ⅱ)

Focus on the Progress of miRNA Research Made by Scientists in Recent Years (Ⅱ)

Measuring two miRNA molecules in blood can be used to assess absorbed ionizing radiation dose

Nuclear radiation and radioactive fallouts resulting from a nuclear weapon detonation or reactor accidents could lead to injuries affecting multiple sensitive organs, defined as acute radiation syndrome (ARS). Rapid and early assessment of injuries to sensitive organs using markers of radiation response is essential for identifying individuals who could potentially exhibit ARS; however, there are no biodosimetry assays approved for human use. In a new study, researchers from Ohio State University have developed a sensitive microRNA (miRNA)–based blood test to measure absorbed ionizing radiation dose in mice. These results were published in the journal Science Translational Medicine.

For many years, several radiation dose-responsive metabolites, proteins, lipids, and mRNAs have been identified as putative biomarkers, however, with less than appreciable sensitivity and robustness over a wide dose range, and the responses reported for many are limited to a narrow analytical range. Researchers developed a sensitive miRNA-based blood test for radiation dose reconstruction with ±0.5 Gy resolution at critical dose range. Using complementary screening platforms such as NanoString nCounter assay, qRT-PCR, and next-generation sequencing-based approaches, they have identified the dose-dependent depletion of serum or plasma expression of miR-150-5p in rodent and nonhuman primate (NHP) models. Radiation dose-dependent changes in miR-150-5p in blood were internally standardized by a miRNA, miR-23a-3p, that was nonresponsive to radiation. Experiments have shown that using a drop of blood from mice, dose estimates can be made from hours to a week after exposure. Leukemia specimens from patients exposed to fractionated radiation showed a loss of miR-150-5p in the blood. They bridged the exposure of these patients to fractionated radiation by comparing responses of mice after fractionated versus single acute exposure. This study suggests the potential utility of this method in radiation disaster management and clinical applications.

Reference

  1. Yadav M, et al. Two-miRNA–based finger-stick assay for estimation of absorbed ionizing radiation dose. Science Translational Medicine, 2020, 12(552).

The ZSWIM8 ubiquitin ligase mediates target-directed microRNA degradation

In a new study, researchers in David Bartel's lab at Whitehead Institute show that mRNAs and other RNAs often turn the tables on their microRNA regulators—and show that the path to microRNA degradation is not what scientists expected it to be. The results were published in the journal Science.

MicroRNAs usually control gene expression by binding to mRNA transcripts, and then working with a protein called Argonaute (AGO) to "silence" those transcripts by causing them to be more rapidly degraded. Although the association with AGO typically protects miRNAs from nucleases, extensive pairing to some unusual target RNAs can trigger miRNA degradation. This phenomenon, known as target-directed microRNA degradation, or TDMD, happens naturally in cells, and is a way to control how much of certain microRNAs are allowed to persist at any given time.

In this study, researchers found that this target-directed miRNA degradation (TDMD) required the ZSWIM8 Cullin-RING E3 ubiquitin ligase. This and other findings showed and supported a mechanistic model of TDMD in which target-directed proteolysis of AGO by the ubiquitin-proteasome pathway exposes the miRNA for degradation. Moreover, loss-of-function studies indicated that the ZSWIM8 Cullin-RING ligase accelerates the degradation of numerous miRNAs in cells of mammals, nematodes, and flies, thereby specifying the half-lives of most short-lived miRNA.

Reference

  1. Shi C Y, et al. The ZSWIM8 ubiquitin ligase mediates target-directed microRNA degradation. Science, 2020.

miR-708-5p targets oncogenic prostaglandin E2 production could lead to new ways to fight lung cancer

Recently, in a research report published in the international journal Oncotarget, scientists from Rutgers Biomedical & Health Sciences found that high level of miR-708-5p (miR-708) expression is directly related to the survival rate of patients with lung squamous cell carcinoma, and miR-708 can inhibit the production of Prostaglandin E2 (PGE2) by inhibiting the expression of Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1) in lung cancer cells.

miR-708 and the arachidonic acid pathway.Figure 1. miR-708 and the arachidonic acid pathway. (Monteleone N J, 2020)

Arachidonic acid metabolism (AA) pathway is a commonly dysregulated inflammatory pathway in lung cancer. AA is released from cellular membranes into the cytosol by the Phospholipase A2 family of enzymes, and then can be metabolized by COX-2, the rate limiting enzyme of prostaglandin production, to prostaglandin H2 (PGH2). The downstream enzyme mPGES-1 metabolizes PGH2 into biologically active PGE2. Although researchers have identified PGE2's pro-tumorigenic functions, the mechanisms governing overexpression of COX-2 and mPGES-1 are incompletely understood. Interestingly, miR-708 is predicted to target both COX-2 and mPGES-1. In this study, researchers show that high miR-708 expression is associated with survival rates in lung squamous cell carcinoma patients. miR-708 also represses PGE2 production by suppressing both COX-2 and mPGES-1 expression in lung cancer cells. miR-708 regulation of COX-2 and mPGES-1 is mediated through targeting of their 3' UTRs. Besides, miR-708 restoration suppresses proliferation, survival, and migration of lung cancer cells. miR-708-induced changes can partially be contributed to its targeting of pro-oncogenic PGE2 signaling. In conclusion, these data suggested that dysregulated miR-708 expression contributes to exacerbated PGE2 production, resulting in an enhanced pro-tumorigenic phenotype in lung cancer cells.

Reference

  1. Monteleone N J, Lutz C S. miR-708-5p targets oncogenic prostaglandin E2 production to suppress a pro-tumorigenic phenotype in lung cancer cells. Oncotarget, 2020, 11(26): 2464.

Scientists uncover the molecular mechanism of microRNA protecting the integrity of blood vessels

miRNAs play a key role in the regulation of gene expression. Abnormal expression and function of miRNAs are often involved in a variety of pathological processes, including the occurrence of chronic diseases such as atherosclerosis. The regulatory function of miRNAs usually occurs in the cytoplasm. In the cytoplasm, miRNAs can interact with target RNA transcripts to inhibit protein production and promote the decline of RNA transcripts.

In a research report published in the international journal Science Translational Medicine, scientists showed that miR-126-5p sustains endothelial integrity in the context of high shear stress and autophagy. Bound to argonaute-2 (Ago2), miR-126-5p forms a complex with Mex3a, which occurs on the surface of autophagic vesicles and guides its transport into the nucleus. In the nucleus, miR-126-5p dissociates from Ago2 and binds to caspase-3 in an aptamer-like fashion with its seed sequence, preventing dimerization of the caspase and inhibiting its activity to limit apoptosis. The antiapoptotic effect of miR-126-5p outside of the RNA-induced silencing complex is important for endothelial integrity under conditions of high shear stress promoting autophagy: ablation of Mex3a or ATG5 in vivo attenuates nuclear import of miR-126-5p, aggravates endothelial apoptosis, and exacerbates atherosclerosis.

Therefore, by inhibiting Caspase-3, miR-126-5p of the nucleus can protect endothelial cells from induced cell death. In addition, it can reduce the sensitivity of endothelial cells at high shear stress sites to injury, which is indeed a mechanism to protect the body against atherosclerosis.

Reference

  1. Santovito D, et al. Noncanonical inhibition of caspase-3 by a nuclear microRNA confers endothelial protection by autophagy in atherosclerosis. Science Translational Medicine, 2020, 12(546).

Related Services

For research use only. Not intended for any clinical use.