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Research progress of MicroRNA in oral diseases









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发表于 2018-9-15 20:27:12 | 显示全部楼层 |阅读模式
MicroRNA is a sequence of 19 to 25 endogenous small non-coding ribonucleotide and regulates the translation of target RNA messenger (mRNA), which has become a key negative post-transcriptional regulatory factor for gene expression. MicroRNA is an attractive therapeutic target, as it can be stabilized between individuals of the same species in serum, plasma, urine and saliva samples in repetitive and consistent forms, and can be further used as a biomarker for clinical diagnosis and disease surveillance. MicroRNA plays an important role in the genetic control mechanism of oral diseases such as periodontal diseases, oral lichen planus, oral cancer, dental pulp and root tip diseases, and oral orthodontics. The latest advances in oral diseases of microRNA are summarized below.
1. The mirna is introduced
1.1 mirna structure
MicroRNA is a non-coding ribonucleotide sequence of 19 to 25 endogenous small ribonucleotides and the translation of target RNA messenger (mRNA), which is used as an endogenous epigenetic gene expression regulator. Studies have shown that they can combine in a way that regulates the expression of about 30 percent of protein-coding genes. The first described microRNA (lin-4) and its regulatory function were reported in 1993 by victor ambrose and Gary ruverkun in the study of caenorhabditis elegans. So far, 35,828 mirnas from 223 species have been identified, including thousands of in humans. Has become a key negative post-transcriptional regulator of gene expression.
1.2 mirnas
MiRNA biogenesis is the process of pri-mirna successively cutting to first produce premiRNA, and then cutting to produce mature miRNA. The process begins in the nucleus, where pri-mirna is transcribed by RNA polymerase II. Pri-mirna is A primary transcriptional material with 5'-cap and 3'-poly-A tail and contains local hairpin structures that encode miRNA sequences. The microprocessor complex composed of Drosha and DiGeorge syndrome chromosomal region 8 (DGCR8) subsequently cut pri-mirna to produce the precursor miRNA. The pre-mirna was then exported from the nucleus to the cytoplasm via exportin-5. Once in the cytoplasm, the pre-mirna, known as Dicer, is further cut into 18-25 nucleotide long double stranded RNA (dsRNA). A strand of the double strand of the hairpin is loaded into the Argonaute (AGO) protein to form an rna-induced silencing complex (RISC), and mature mirnas incorporated with RISC are capable of targeting mRNA by base pairing.
1.3 mirna function
The six nucleotides in the microRNA5 'terminal are called "seed sequences" that specifically bind to the 3' UTR of the target mRNA, targeting degradation or translation regulation. Most mirnas affect gene expression through gene silencing mechanisms, including through RISC mRNA cutting and translation inhibition. MiRNA post-transcriptional gene regulation mediated by RNA interference is considered to be inevitable in normal cellular physiology, providing an effective pathway for post-transcriptional level regulation of gene expression. MicroRNA can inhibit messenger mRNA translation, stabilize or induce its degradation, and play a key role in development and cell homeostasis. It regulates genetic expression and participates in the control of cell function (epithelium and interstitial transformation and differentiation, proliferation, apoptosis and metabolism).
MicroRNA is involved in tumor development and cardiovascular function, cancer, diabetes, oral diseases, obesity and neurological disorders. In recent years, miRNA has become a regulator of many complex biological processes involving cross coordination and functional integration of complex physiological events.
1.4 principles of microRNA regulation
The expression and function of miRNA in different cells, tissues or diseases may show heterogeneity, indicating the complex regulatory mechanism of miRNA and target mRNA. First, each miRNA can act on many target mrnas. Second, a single mRNA is typically targeted by multiple mirnas, which allows for significant combinatorial complexity and regulatory potential. Furthermore, the predicted miRNA/mRNA targets are not necessarily limited to specific functional categories or biological pathways. Finally, miRNA may be mainly responsible for "fine-tuning" gene expression in the regulation of development and tissue homeostasis.
2. Periodontal disease
Periodontal disease is one of the most common oral diseases in the world. Several studies have shown that microRNA plays an important role in the pathogenesis of periodontal disease. MiRNA kinetics in periodontal tissues and mechanisms related to periodontitis has been extensively studied, however, the role of miRNA in periodontal disease remains to be elucidated. Kalea et al. reported that the miRNA spectrum of gingival tissue of obese patients with periodontitis showed 13 up-regulated and 22 down-regulated mirnas compared with patients with normal weight, and confirmed that mir-200b target gene was involved in biological pathways related to wound healing and angiogenesis. Du et al. studied the identification of 22 upregulated and 28 down-regulated mirnas in PDLC (human periodontal membrane cells) treated with porphyromonas gingivalis to increase the understanding of the role of miRNA as a key regulator of lps-induced periodontitis.
It has been reported that mir-132 induced by porphyromonas gingivalis regulates the pathogenesis of periodontitis by regulating tumor necrosis factor TNF. Another study indicated that mir-142 also induced apoptosis of human gingival epithelial cells by targeting BACH2, which may represent a potential therapeutic target for periodontitis. In a recent study, the rat model of periodontitis provided evidence of a direct relationship between proinflammatory factors and the expression of mir-138 in periodontal ligament progenitor cells, and established a potential mechanism for mir-138 to regulate periodontal mineral homeostasis under inflammatory conditions, suggesting that mir-138 inhibitors can be used as potential therapeutic agents to prevent bone loss related to advanced periodontal disease.
Jiang et al. showed that mir-146a plays a negative feedback role in the regulation of pro-inflammatory cytokines secretion in human periodontal cells after gingival porphyrin polysaccharide stimulation. Tomofuji et al. proposed that serum miRNA (mir-207, mir-495 and mir-376b-3p) may be a valuable biomarker for periodontitis, and proposed that the changes of miRNAs in periodontitis may reflect the progress of periodontal tissue destruction rather than the occurrence of periodontitis. Studies have assessed the association between mir-146a and mir-196a2 genomic single-nucleotide polymorphism (SNP) in patients with chronic periodontitis. Nayar et al. were the first to show that primary periodontal infection can alter the miRNA profile of secondary sites such as salivary glands and pancreas, highlighting the complex correlation between periodontal disease, diabetes and sjogren's syndrome.
3. Lichen planus
Oral lichen planus (OLP) is a chronic inflammatory disease of oral mucosa endothelium. Oral lichen planus is classified as a "potential precancerous disease" with considerable risk of malignant transformation and therefore requires regular monitoring. Byun et al. studied the potential miRNA biomarkers of exosomes from oral lichen planus, and identified three mirnas (mir-4484, mir-1246 and mir-1290) that provided the role of miRNA in the pathogenesis of oral inflammation. Liu et al. identified mir-362 targeting SRGAP2 and VAMP4 as a potential risk miRNA for OLP regulation. The potential regulatory relationships between differentially expressed genes (DEGs) and differentially expressed miRNA (DEM) were also investigated.
Shen et al. first reported that the abnormal expression levels of mir-562 and mir-203 were correlated with the high expression of il-22, suggesting that il-22 and its targeted miRNA are conducive to the study of the pathogenesis of OLP. Studies have suggested that the expression profile of miRNA encoded by HCMV (human cytomegalovirus) in plasma samples of OLP patients is different from the normal control group. Studies have shown that the downregulation of mir-138 increases the expression of cell cycle protein D1 in OLP mucosa, which may play a key role in the pathogenesis of the disease. Wang et al. confirmed that mir-125b in lps-induced OLP model targets mmp-2 expression through PI3K/Akt/mTOR pathway, inhibits proliferation of keratinocytes and promotes apoptosis of keratinocytes, suggesting that mir-125b is a potential therapeutic target for OLP therapy.
Oral squamous cell carcinoma
Oral squamous cell carcinoma (OSCC) is a common malignant tumor. There has been no substantial improvement in diagnosis and treatment over the past few decades. Previous studies have shown that abnormally expressed cancer-related microRNA may be related to the occurrence and development of OSCC. One study showed that mir-200c-3p has potential transmission and invasion in the microenvironment of oral squamous cell carcinoma. A literature review of 30 cases of OSCC investigated the correlation between miRNA expression and clinical tumor parameters. Different expressions of mir-99, mir-224 and mir-205 in tumors indicated that they might be used as biomarkers.
Yang et al. reported that mir-381-3p was down-regulated in OSCC. By inhibiting FGFR2 as a tumor growth inhibitor, the newly discovered mir-381-3p /FGFR2 provided an understanding of the pathogenesis of oral cancer and a potential therapeutic target for OSCC. Recent studies have shown that the specific combination of mir-486-3p, mir-139-5p and mir-21 achieves the best results in differentiating TSCC and non-cancer tissue samples, which may lead to early detection and prevention of oral cancer. Zhou et al. found that mir-221/222 might down-regulate the expression of PTEN (homologous tension protein) in OSCC cells, providing new insights into the potential mechanism of OSCC tumorigenesis. Other studies reported that mirna-375 inhibits growth by targeting insulin-like growth factor 1 receptor igf-1r and enhances the radiosensitivity of OSCC cells, indicating that mir-375 may be a potential therapeutic target for OSCC patients.
5. Periapical disease of tooth pulp
The role of microRNA in periapical diseases of dental pulp has been studied more recently. Wang et al. found differences in miRNA expression in human dental pulp cells in the elderly and young adults, and mir-433 is considered a potential target for promoting the regeneration and repair capacity of aging dental pulp cells. Yue et al. found different miRNA expression profiles between apical lesion and human periodontal fibroblast inflammation. In addition, mir-155 may become a target for the treatment of apical lesions through foreign body mediated transmissions. One study suggested that mir-335-5p may play a dual role in periapical inflammation by directly targeting uPAR and RANKL, which are highly correlated with inflammation and bone destruction, and that mir-335-5p may be a potential therapeutic target for apical lesions. These findings provide new insights into the pathogenesis of pulp lesions and may determine potential therapeutic targets for future studies.
6. Other
In vivo studies of Chen et al. showed that periodontal mir-21 was sensitive to orthodontic force and periodontal inflammation during tooth movement, and regulated the osteogenesis of periodontal stem cells after orthodontic movement. The possible role of mir-29 family as a homeostasis regulator of periodontal extracellular matrix in alveolar bone reconstruction during orthodontic movement was studied. Schoen et al. compared miRNA expression in palatal fibroblasts from cleft palate patients and age-matched controls, requiring large-scale genomic and expression studies to verify their findings. The study of saliva miRNA spectrum of high and low oral health quality of life indicated that the expression of mir-203a-3p in saliva could reflect oral quality of life.
7. Outlook
The stability of microRNA in biological fluids such as serum, plasma and saliva, and gingival crevicular fluid makes it a potential noninvasive biomarker. MiRNA not only has experimental or diagnostic value, but also has great potential to treat diseases, including oral diseases. As therapeutics, individual miRNA can target several genes and affect multiple regulatory networks, while the combination of miRNA or its antagonist can be used to regulate several members of the same signal transduction pathway, affect many biological cascades, and prove the importance and complexity of post-transcriptional regulation of miRNA. These studies provide the basis for potential treatment. However, direct and indirect targets of miRNAs for different pathways of transduction and communication between miRNA and intracellular signals should be further investigated, and real targets should be found in specific tissue types, and accurate expression patterns should be determined as necessary to develop effective and practical therapeutic approaches. Downregulation or antagonism of disease-related mirnas and application of exogenous mirnas that mimic endogenous beneficial mirnas. On the other hand, the administration of miRNA inducers that increase tissue specific miRNA expression may be an alternative treatment for related diseases, but there are still significant challenges. But the next few years will see the development of mirn-based therapies, which can be used to treat metabolic, autoimmune and degenerative diseases, cancer and many other characteristics after testing for safety and efficacy in animal models.


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