miR-324-5p is a microRNA that functions in cell growth, apoptosis, cancer, [1] epilepsy, [2] [3] neuronal differentiation, [4] psychiatric conditions, [5] cardiac disease pathology, [6] [1] and more. [7] As a microRNA, it regulates gene expression through targeting mRNAs. Additionally, miR-324-5p is both an intracellular miRNA, meaning it is commonly found within the microenvironment of the cell, and one of several circulating miRNAs found throughout the body. [8] Its presence throughout the body both within and external to cells may contribute to miR-324-5p's wide array of functions and role in numerous disease pathologies – especially cancer – in various organ systems.
miR-324-5p first appeared in literature in a paper published by John Kim et al. in early 2004 that identified 32 entirely new miRNAs from cultured rat cortical neurons using miRNA cloning and RNA analysis. [9] The miRNA quickly gained traction in scientific literature, appearing in articles about the evolutionary conservation of microRNAs, [10] HIV, [11] cancer, [12] and other topics within a few years. Today, the functions and roles of miR-324-5p are still not yet fully characterized. [13]
miR-324-5p is a reverse strand miRNA, meaning it is produced from the 5' end of the associated RNA, and spans from position 7,223,342 to 7,223,364 on chromosome 17. [14] Its sequence is CGCAUCCCCUAGGGCAUUGGUG. [15] [16]
miRNA forms following cleavage of pre-miRNA at the hairpin loop by the enzyme dicer within the cytosol. Interestingly, both strands of miR-324's pre-miRNA hairpin loop structure, miR-324-5p and miR-324-3p, become active miRNAs with distinct targets and functions. [17] miR-324-5p has between 166 and 469 predicted targets, [18] [19] [14] including regulators of cell growth, proliferation, survival, cytoskeletal structure, ATP transport, and ion channels. [18] Though miR-324-5p is found on chromosome 17, its targets span across all chromosomes. [16]
miR-324-5p likely regulates cell growth and survival through interaction with multiple pathways. Published research demonstrates that this miRNA interacts with the Hedgehog (HH) signaling pathway via interactions with HH transcription factor Gli1 [20] and HH protein receptor Smo, [21] often contributing to tumorigenesis. miR-324-5p's activating interaction with the protein NfkB also regulates numerous components of cell survival, including cell cycle control, enzyme synthesis, and cell adhesion. [22] In addition, miR-324-5p regulates components of the MAPK pathway, influencing cell growth, proliferation, and survival. Specifically, miR-324-5p downregulates RAF and ERK and is necessary for normal levels of cell growth. Reduced expression leads to increased cell growth and proliferation, and overexpression limits growth, leading to its role in oncogenesis. [23]
Both up and downregulation of miR-324-5p is shown to contribute to various types of cancer. [17]
miR-324-5p plays a role in inflammation and tumorigenesis in colorectal cancer through regulation of CUEDC2, which regulates inflammation via interaction with NF-kB signaling. [12] miR-324-5p can inhibit glioma proliferation, [20] suppress hepatocellular carcinoma and nasopharyngeal carcinoma cell invasion, [24] [25] and regulate growth and pathology in multiple myeloma. [26] Additionally, chromosome 17 deletions, which include deletion of miR-324-5p, are present in 10% of multiple myeloma patients and are associated with poorer prognosis. [26]
In contrast, overexpression of miR-324-5p in gastric cancer cells reduces cell death and promotes growth and proliferation. [27] miR-324-5p has also been shown to reduce the viability of gastric cancer cells via downregulation of TSPAN8, and miR-324-5p expression increased apoptosis in these same gastric cancer cells. [28]
Seizures are characterized by high levels of synchronized neuronal activity. One important regulator of neuronal activity is the hyperpolarizing A-type current mediated by potassium channel KV4.2. [29] miR-324-5p downregulates KV4.2, exacerbating conditions that lead to seizure onset, and downregulation of miR-324-5p in mouse models of epilepsy is seizure-suppressive. [3]
Changes in miRNA expression are seen in epileptogenesis and in other disease pathologies. [30] [31] In epilepsy, miR-324-5p expression has been shown to increase [32] and decrease [33] at different timepoints and loci.
Importantly, miR-324-5p has increased association with the RISC complex following seizure in mice, indicating more suppressive activity. [3] [34]
Overall, this suggests that miR-324-5p plays a role in epileptogenesis via targeting of potassium channel KV4.2.
miR-324-5p contributes to cardiac disease pathophysiology and cardiomyocite death through translational inhibition of Mtfr1, leading to reduced mitochondrial fission, apoptosis, and myocardial infarction. [6]
MiRNA expression profiles are altered in psychiatric conditions, including depression, [5] anxiety, [35] and PTSD. [36] It has been demonstrated that miR-324-5p expression is altered in the brains of suicide victims with depression [5] and in the amygdala, the fear center of the brain, in PTSD. [36] MiRNAs are an underexplored potential biomarker and target for treatment for psychiatric disease. [37]
miRNA-324-5p is a relatively new and understudied microRNA. It is an important regulator in several diseases, and its effects span across the body from neuronal dysregulation in seizure to hepatocellular carcinoma and cardiac disease. Because microRNAs have numerous targets, they are capable of regulating multiple pathways and circuits, an ability that may be useful in the treatment of complex disorders like epilepsy in which many subsystems are dysregulated. However, the wide-ranging functions of miRNAs may be limiting as well. microRNA expression modulation could lead to unanticipated physiological effects and not provide adequate specificity. [38]
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The miR-124 microRNA precursor is a small non-coding RNA molecule that has been identified in flies, nematode worms, mouse and human. The mature ~21 nucleotide microRNAs are processed from hairpin precursor sequences by the Dicer enzyme, and in this case originates from the 3' arm. miR-124 has been found to be the most abundant microRNA expressed in neuronal cells. Experiments to alter expression of miR-124 in neural cells did not appear to affect differentiation. However these results are controversial since other reports have described a role for miR-124 during neuronal differentiation.
The miR-129 microRNA precursor is a small non-coding RNA molecule that regulates gene expression. This microRNA was first experimentally characterised in mouse and homologues have since been discovered in several other species, such as humans, rats and zebrafish. The mature sequence is excised by the Dicer enzyme from the 5' arm of the hairpin. It was elucidated by Calin et al. that miR-129-1 is located in a fragile site region of the human genome near a specific site, FRA7H in chromosome 7q32, which is a site commonly deleted in many cancers. miR-129-2 is located in 11p11.2.
The miR-17 microRNA precursor family are a group of related small non-coding RNA genes called microRNAs that regulate gene expression. The microRNA precursor miR-17 family, includes miR-20a/b, miR-93, and miR-106a/b. With the exception of miR-93, these microRNAs are produced from several microRNA gene clusters, which apparently arose from a series of ancient evolutionary genetic duplication events, and also include members of the miR-19, and miR-25 families. These clusters are transcribed as long non-coding RNA transcripts that are processed to form ~70 nucleotide microRNA precursors, that are subsequently processed by the Dicer enzyme to give a ~22 nucleotide products. The mature microRNA products are thought to regulate expression levels of other genes through complementarity to the 3' UTR of specific target messenger RNA.
The miR-1 microRNA precursor is a small micro RNA that regulates its target protein's expression in the cell. microRNAs are transcribed as ~70 nucleotide precursors and subsequently processed by the Dicer enzyme to give products at ~22 nucleotides. In this case the mature sequence comes from the 3' arm of the precursor. The mature products are thought to have regulatory roles through complementarity to mRNA. In humans there are two distinct microRNAs that share an identical mature sequence, and these are called miR-1-1 and miR-1-2.
The miR-34 microRNA precursor family are non-coding RNA molecules that, in mammals, give rise to three major mature miRNAs. The miR-34 family members were discovered computationally and later verified experimentally. The precursor miRNA stem-loop is processed in the cytoplasm of the cell, with the predominant miR-34 mature sequence excised from the 5' arm of the hairpin.
microRNA 21 also known as hsa-mir-21 or miRNA21 is a mammalian microRNA that is encoded by the MIR21 gene.
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MiR-155 is a microRNA that in humans is encoded by the MIR155 host gene or MIR155HG. MiR-155 plays a role in various physiological and pathological processes. Exogenous molecular control in vivo of miR-155 expression may inhibit malignant growth, viral infections, and enhance the progression of cardiovascular diseases.
In molecular biology mir-126 is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several pre- and post-transcription mechanisms.
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