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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 13  |  Issue : 2  |  Page : 101-107

Biogenesis of microRNAs and its implication in head and neck pathologies: A Narrative Review


Department of Oral & Maxillofacial Pathology, Kalinga Institute of Dental Sciences, Kalinga Institute of Industrial Technology Deemed To Be University, Bhubaneswar, Odisha, India

Date of Submission29-Jun-2020
Date of Decision28-Oct-2020
Date of Acceptance28-Dec-2020
Date of Web Publication17-Apr-2021

Correspondence Address:
Dr. Kailash Chandra Dash
Department of Oral & Maxillofacial Pathology, Kalinga Institute of Dental Sciences, Kalinga Institute of Industrial Technology Deemed To Be University, Bhubaneswar, Odisha.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jioh.jioh_226_20

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  Abstract 

Aim: MicroRNAs (miRNA) are 19–23 nucleotides small non-coding RNAs that regulate gene expression either by silencing or degrading the target gene. Altered miRNAs are associated with various dental and inflammatory diseases. The aim of this review is to provide an insight into the biogenesis, role of miRNA in physiology, and development of dysregulated miRNA which has an impact on hallmarks of cancer. Materials and Methods: A literature review search was made from PubMed, Scopus, and Web of Science databases using the key words biogenesis of miRNA, stem cell culture, oral cancer, circulating miRNAs, autoimmune disorders, and periodontitis. We also included systematically reviewed articles that highlighted the mechanism of silencing of gene and epigenetic modifications by miRNA. Results: Pertaining to various literatures there is definite correlation of miRNA with various pathological conditions occurring in head and neck region. Conclusion: Our review indicates that numerous miRNAs play a key role in diagnosis, prognosis, and therapeutic role in oral diseases. In this context, multitudinous studies are a prerequisite for validation of miRNA as a reliable biomarker in head and neck pathologies and its targeted therapy.

Keywords: Biomarker, circulating miRNA, miRNAs, non-coding RNA


How to cite this article:
Mahapatra N, Dash KC, Bhuyan L, Behura SS, Mishra P, Panda A. Biogenesis of microRNAs and its implication in head and neck pathologies: A Narrative Review. J Int Oral Health 2021;13:101-7

How to cite this URL:
Mahapatra N, Dash KC, Bhuyan L, Behura SS, Mishra P, Panda A. Biogenesis of microRNAs and its implication in head and neck pathologies: A Narrative Review. J Int Oral Health [serial online] 2021 [cited 2021 Jun 17];13:101-7. Available from: https://www.jioh.org/text.asp?2021/13/2/101/313838


  Introduction Top


Molecular biology consists of three macromolecules: deoxyribonucleic acid (DNA), the genetic material of all living organisms; ribonucleic acid (RNA), transmits genetic information from DNA to the cytoplasm to be converted into amino acids and protein, a sequence of amino acids which forms the structural and functional basis of every cell. For decades it was thought that RNA plays a very minor role in gene expression. In late 1960s, a subset of RNAs was found to control gene expression by specifying which genes to turn on and which to turn off. These non-coding RNAs are so called as they do not code proteins. They are a distinct class which can be classified as small RNAs which are micro RNA (miRNA) including small temporal RNA (stRNA), short interfering RNA (siRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), and transcriptional RNA such as transfer RNA (tRNA), ribosomal RNA (rRNA), and long non-coding RNA (long nc RNA).[1]

Following completion of the human genome project, it was found that there are approximately 1,000 genes in humans that encode miRNAs, accounting for about 3% of the human genome. miRNAs are small non-coding RNAs of 19–24 nucleotide in length. They bind to the 3′-UTR of the target mRNA which then down regulate the translation of proteins, thus, regulating gene expression and also influence epigenetic mechanisms. Hence, a given miRNA can silence many target genes.[2],[3] Apart from their availability in tissues, miRNAs are also found in body fluids like saliva, plasma, and serum in stable form as extracellular micro particles or bound to lipoproteins which can be easily extracted and harnessed as diagnostic or prognostic markers of various malignancies.[4] In this review, we have consolidated the findings from various studies and literature reviews on miRNA from Pub Med, Scopus, and Web of Science indexed journals using the key terms like miRNA biogenesis, role of miRNA in physiology and homeostasis, correlation of miRNA and oral cancer and its upregulation and downregulation in regulation of genes implicated in oral cancer, circulating miRNAs and role of miRNA in autoimmune disorders and periodontitis. We have included all the relevant literature available in the said data bases from 2010 to recent 2020 by various authors. We have excluded the clinical studies.There are very few publications that have depicted on the role of miRNAs in Head and Neck Pathologies. This narrative review shows an insight of such role of miRNAs.


  History Top


The first miRNA, lin-4 (abnormal cell lineage) was discovered by Ambros and co-workers in Caenorhabditis elegans as an endogenous regulator of genes that control developmental timing.[5] The second miRNA, let-7 was discovered and found to function similar to lin-4. Thereafter, the direct conversion of dsRNA into 21–23 nt siRNA was documented. In 2001, miRNA was found to consist of a broad class of small RNA regulators.[6],[7],[8] Currently there are over 38,589 miRNA (mature and hair pin) sequences listed in the miRNA registry identified by molecular cloning.[9],[10] Thus a single miRNA controls the expression of many mRNA transcripts because it does not require perfect sequence complementarity.[11],[12] The origin and target of small non-coding RNA is outlined in [Table 1].
Table 1: miRNA and siRNAs

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  Biogenesis of miRNAs Top


miRNA is produced through transcription of miRNA genes in the nucleus known as miRNAs precursor genes (mir-gene). Intergenic miRNAs are transcribed into pri-miRNAs, which are longer nucleotide sequences by RNA polymerase II. These are then spliced and capped with a 5′ 7-methylguanosine cap and polyadenylated at the 3′ end. The primary miRNAs form specific hairpin-shaped stem loop secondary structures into pre-miRNAs. The microprocessor complex consisting of Drosha and the essential cofactor DGCR8/pasha that process the primary miRNAs into 60- to 70-nucleotide long pre-miRNA with a 5′ phosphate and a 3′ nucleotide overhang. Exportin 5 transports the pre-microRNA to the cytoplasm. In the cytoplasm, dicer processes the pre-microRNA into short double-strand microRNA, along with its partner protein TRBP (trans-activator RNA binding) followed by the unwinding of the duplex by a helicase to reveal the final mature microRNA. Dicer also initiates the formation of the RNA-induced silencing complex (RISC).[7],[8],[9] The mature microRNA is asymmetrically incorporated into RISC and transferred to the target mRNA.[9],[11] Only one strand of the duplex is incorporated into a RISC to bind 3′ UTR of target genes and suppress expression, while the other strand is normally degraded. A key component of the RISC is the argonaute (Ago) family of proteins. In the mammals, there are four Ago proteins (Ago1- 4), but only Ago 2 is known to function in the miRNA and siRNA pathways. Ago2 has been shown to cleave mRNA targeted by miRNA or siRNA and is known as the catalytic enzyme of RNA interference (RNAi).The argonaute proteins prevent the degradation of RISC—loaded mature miRNA. miRNAs are manufactured by two Drosha independent, non-canonical/alternative pathways. In the first pathway, the initial processing step is done by spliceosome and debranching enzyme that produce a short hairpin which is further processed by dicer. These miRNAs are termed asmirtrons. In the second pathway, short hairpin RNAs are prepared by unknown nucleases into pre-miRNAs that produce miRNAs by dicer. These miRNAs are termed as endogenous short hairpin RNA (shRNA)-derived miRNAs.[12],[13],[14]


  Mechanism of Gene Regulation Top


The degree of complementarity between the miRNA and its target determines the mechanism of binding and silencing. Guided by the sequence complementarity between the small RNA and the target mRNA, miRNA-RISC-mediated gene inhibition is commonly divided into three processes: site-specific cleavage, enhanced mRNA degradation, and translational inhibition. The first process is restricted to miRNAs with a perfect and near perfect match to the target RNA (commonly referred to as RNAi). In contrast, the other two processes are more commonly associated with mismatch miRNA/target sequences. The combination of these two processes is commonly referred to as non-cleavage repression and is carried out by Ago proteins. miRNAs and siRNAs involved in RNAi use the same RISC to direct silencing. Hereafter, the mechanism diverges miRNAs, attach imperfectly to mRNA, and form a bulge that block mRNA to produce protein while siRNA binds perfectly with the target mRNA.[14],[15],[16] The miRNAs can be detected using both traditional methods (northern blotting, microarray analysis, and quantitative polymerase chain reaction) and advanced technology methods (signal amplification strategies). This recent development in detection methods will help in improving the sensitivity and selectivity of miRNA determination.[3],[17]


  Role in Physiology Top


miRNAs are involved in the regulation of almost all major cellular functions, such as cell differentiation, proliferation/mobility, and apoptosis.[18] They are suggested to play a role in specifying tissue identity. Expression of a known miRNA in a specific cell type plays a useful marker for identifying a particular cell type.[19]

Researchers have identified a code of miRNAs required for tooth patterning, size, shape, and number. Gene knockout studies in mice revealed that the cervical loop region contains specific sets of miRNAs that regulate cell differentiation.[20] The self-renewing divisions of stem cells are controlled by both intercellular and intracellular mechanisms. Recently, miRNAs have emerged as important players in translational regulation and have implications in controlling stem cell fate and behavior.[21] RE1-silencing transcription factor (REST), a transcriptional repressor, down regulates miR-21, which targets Nanog, SOX2, and OCT4 which are essential for stem cell self-renewal. miR-296 promotes embryonic stem cell (ES cell) differentiation and miR-22 inhibits ES cell differentiation.[22] Functional inhibition of miR-138 can accelerate osteogenic differentiation in vivo. Thus, miR-138 can be useful for therapeutic approaches in pathological conditions of bone loss.[23]


  Role in Pathology Top


miRNAs are highly conserved class of 19-23nt, small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level by binding to 3′UTR of target mRNAs and resulting in mRNA cleavage or inhibition of protein synthesis.[24],[25] The difference in gene regulation causes genotypic and phenotypic variations among individual of same species and also is the reason for regulation of disease.[26]


  Significance of miRNA in Head and Neck Squamous Cell Carcinoma Top


In humans, homeostasis is maintained by a balance between cell proliferation and programmed cell death. Collapse in this homeostasis results in tumorigenesis.[27] Trotta et al.[28] suggested that oral cancer mostly originating in floor of mouth accounted for 70% of oral carcinoma. In USA, 75% of oral squamous cell carcinoma was seen in lower lip, tongue, and floor of mouth in decreasing frequency.[29] In India, the most common sites were buccal mucosa, followed by retromolar area, floor of the mouth, lateral border of the tongue, labial mucosa, and palate.[30] Hanahan and Weinberg[31] suggested the hallmark of cancer comprising of six steps which include sustaining proliferation signaling, evading growth suppression, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion, and metastasis.

The altered miRNA expression can affect these hallmarks for initiation and progression of malignant tumors. The underlying mechanism of dysregulated miRNA include abnormalities in chromosome, epigenetic changes, defect in biogenesis of miRNA, and trancriptional control changes.[32]

Chromosome abnormality

Aberrant miRNA expression was discovered mainly due to alterations in miRNA genome. This can be because of amplification, deletion, or translocation of miRNA gene. Earliest known chromosomal abnormality was loss of miR-15a/16-1 cluster gene at 13q14 and amplification of miR-17–92 cluster gene in B-cell chronic lymphocytic leukemic patients. Similarly, deletion of miR-143 and miR-145 is seen in cancer that reduces the miRNA expression.[32]

Transcriptional changes

In cancer, abnormal miR expression can also be due to dysregulation in transcriptional factors like c-myc and p53. Up regulation of c-myc activates miR-17–92 cluster that regulate cell cycle and apoptosis which is essential in cancer initiation. Similarly, down regulation of miR-148a-5p expression promotes cells from G1 to S phase resulting in tumourigenesis. p53 is known as the guardian of cell that control the cell cycle, apoptosis and helps in DNA repair mechanism. Loss of p53 gene results in loss of tumor suppressor miR-34 that causes progression of cell cycle, evasion of apoptosis which are essential hallmark for tumorigenesis.[32]

miRNA processing defects

Drosha and dicer are the main two RNase III endonucleases that are responsible for miRNA maturation from primary miRNA precursors. Mutation in DGCR8 and Drosha results in abnormal expression of miRNA that most commonly causes decreased expression of mature miR-200, let-7a leading to head and neck squamous cell carcinoma. Dysregulation in dicer results in reduced expression of let-7 that in turn promotes tumor initiation, progression, and metastasis. Several other enzymes like argonuate proteins and exportin -5 also regulate miRNA formation, maturation, and expression. Mutation in these enzymes causes altered expression of miRNA in tumors corresponding to lymph node metastasis.[32]


  Role of miRNA in Oral Squamous Cell Carcinoma Top


Few miRNAs act as tumor suppressors (TS-miRs) and other as oncogenes (oncomiRs). miRNAs play a crucial role in the p53 tumor suppressor pathways. The ability of miRNAs to target many genes may signify that they could be involved in conferring self-renewal of cancer stem cells. The ability of stem cells to bypass the G1/S checkpoint is accomplished via miRNAs. Thus, miRNA play a major role in cancer initiation, progression, diagnosis, prognosis, and therapeutic response.[27] The miRNA that are up regulated in cancer are miR-21, miR-7, miR-34b, miR-155, miR-182, miR15-b, miR-185, and let-7 and conversely other miRNA that are down regulated are miR-23b, miR-125a, miR-125b. Another miR-146 activates toll-like receptor pathway that mediates inflammatory response. Imbalance in this signaling pathway due to abnormal expression of miRNA favors tumor growth and metastasis.[33],[42],[43] The dysregulation in canonical miRNA pathways resulting in pathogenesis of cancer has been illustrated in [Figure 1].
Figure 1: Dysregulated biogenesis machinery of miRNA. miRNA = micro RNA, Xpo5 = exportin 5, TRBP = transactive responsive RNA binding protein, SNP = single nucleo-tide polymorphism, Kras oncogene = Kirsten rat sarcoma virus, mRNA = messenger RNA

Click here to view



  Role of miRNA in Salivary Adenoid Cystic Carcinoma (SACC) Top


The most frequently encountered salivary gland neoplasm is adenoid cystic carcinoma. Patients with SACC have poor prognosis due to high rate of recurrence, metastasis, and perineural invasion. Up regulation of miR-4487, miR-4430, miR-5096, miR-1285-3p, miR-1273f, miR-1273a, miR-1273e, miR-3150 and down regulation of miR-5191, miR-4278, miR-4498, miR-4450 is associated with SACC. Aggressive behavior of tumor was reported to be mostly due to up regulation of miR-455-3p, miR-181, miR-183 and down regulation of miR-375, miR-148, miR-155, miR-29.[33]


  Circulating miRNAs Top


Various authors found 18 to 24nt endogenous miRNA in plasma through the following procedure of cloning, sequencing, and quantification.[34],[35],[36] These circulating miRNAs regulate many biological processes and their quality and quantity changes in pathological status.[35] Depending upon the mechanism of release of miRNA into the circulation, they can be of vesicle-associated and non-vesicle-associated types. The recent studies indicate that membrane bound vesicles function as transporters for exogenous miRNAs. In contrast, other studies confirmed that most circulating miRNA’s are present in non-vesicle associated form. Ago2 along with GW182 has its function in protection and transportation of extracellular miRNAs from degradation in plasma. Wang et al.[37] in 2010 suggested that, the circulating miRNA which are membrane associated aid in cell to cell communication. These encapsulated miRNA have the ability to reach very remote areas and influence the tumor microenvironment that is important in tumorigensis.[37] Several hypothesis have been proposed by various authors supporting the mechanism of extracellular miRNA in cell-to-cell communication which include direct fusion of vesicle with the cell membrane of recipient cell, endocytosis/ phagocytosis by receptor, recognition of proteins in the receptor of recipient cell on exosomal surface, and gap-junction-mediated transfer.[35]

Circulating miRNAs in saliva and plasma are potential biomarkers for head and neck pathological conditions like premalignant lesions, oral cancer, salivary gland neoplasm, periodontitis, various autoimmune diseases like systemic lupus erythematosus, and oral lichen planus.[28],[29] These circulating miRNAs facilitate in early diagnosis and prediction of prognosis in cancer. In oesophageal cancer, miR-223-3p, miR-192-5p, miR-28-3p are up regulated which aid in diagnosis and miR-1246, miR-146a down regulated in cancer which is an indicator for prognosis [Figure 2].[35]
Figure 2: Biogenesis of miRNA and cell-to-cell communication is via exosomes/micro vesicular bodies (MVBs)—green arrow; direct transport theory gap junction of cell—blue arrow; indirect identification of specific cell surface reception—red arrow

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  Role of miRNA in Periodontitis Top


Periodontal tissue undergoes continuous remodeling owing to tissue turnover, mechanical stress, and inflammatory component due to periodontal diseases. Homeostasis of the periodontal region is maintained by balance between the rates of bone degradation and new bone formation. In periodontitis, the homeostasis is disturbed because of host inflammatory response of prostaglandins, cytokines, and chemokines to supragingival and subgingival plaque bacterial pathogens. This results in increased bone resorption and impaired bone formation. As periodontitis process progresses there is acceleration of matrix degradation and destruction eventually resulting in tooth loss. Multiple signaling pathways which include BMP, Wnt, and notch pathways induce osteogenic differentiation. Studies done by various authors suggested that osteogenesis is affected by down regulation of miR-34a, miR-34c, and miR-218 target RunX2.[38] Bae et al.[39] proposed that down regulation of miR-34 induces NOTCH signaling pathway that promotes periodontal progenitors to undergo osteoblastogenesis. miR100 negatively influence BMPR2 and human mesenchymal stem cells. Thus, up regulation of miR100 inversely affect the BMPR2 expression which in turn inhibits RunX2 resulting in decreased osteogenic differentiation. Later it was proposed that upregulation of miR-21 suppresses the SMAD7 and escalate BMP-9 signaling promoting osteogenic differentiation. Other set of miRNA like miR-27, miR-29, and miR-199 upregulation results in down regulation of inhibitors of osteogenic differentiation, that is, Wnt inhibitors promoting bone matrix formation by enhancing Wnt signaling pathway.[38],[44]


  miRNA and Autoimmune Diseases Top


Autoimmune diseases are those conditions in which the host immune system produces antibodies against its own specific organs causing significant tissue/organ damage. Many miRNAs are reported to play a vital role in autoimmune regulation.[40]

Rheumatoid arthritis is characterized by inflammation of synovial tissue causing bone and cartilage destruction. miR-146 and miR-155 are up regulated in patients with rheumatoid arthritis. Demethylation of miR-34 escalates the apoptosis of synovial fibroblasts, which is important for rheumatoid arthritis pathogenesis. miR-124 regulates CDK2 and monocyte protein-1 which is critical in rheumatoid arthritis. Up regulation of miR-203 enhances MMP-1 and IL-6 expression, hence, act as proinflammatory factor in rheumatoid arthritis. The plasma concentration of miR-24 and miR-125 are diagnostic markers of rheumatoid arthritis.[40]

Sjogren’s syndrome is an autoimmune disorder which clinically represents by reduced secretion of salivary and lacrimal gland due to lymphocytic infiltration. It can be classified as primary Sjogren’s syndrome and secondary Sjogren’s syndrome.[33],[41] Sjogren’s syndrome can be used as a study model for various miRNAs using microarray assay. miR-17–92 cluster are down regulated in patients with Sjogren’s syndrome. Conversely, miR146 is upregulated which influences phagocytosis and suppress cytokine production.[40]

Systemic lupus erythematosus is a chronic autoimmune disease with multiple clinical symptoms. Peripheral blood from SLE patients by microarray assay revealed differential expression of HSa-miR-371-5p, HSa-miR-1224-3p, HSa-423-5p miRNAs. There was upregulation of miR-15, miR-148a, and downregulation of miR-146a, miR-155 in peripheral blood SLE patients.[40] The dysregulation and differential expression of various miRNAs in head and neck pathologies have been tabulated [Table 2].
Table 2: Dysregulated miRNA in head and neck pathologies

Click here to view



  Conclusion Top


The majority of miRNAs are intracellular but extracellular miRNAs are also discovered which mediate cell-to-cell communications. The presence of miRNAs in cell secreted small vesicles called exosomes in saliva and variety of bodily fluids have emerged as potential candidate for immunotherapy. This review summarizes the biogenesis and alteration of various miRNAs that are dysregulated in numerous head and neck pathologies and provide an insight in the role played by miRNAs in the pathophysiologic processes. miRNA act as potential non-invasive biomarkers and have diagnostic, prognostic, and therapeutic implications. Thus, miRNAs are at the forefront of modern biology, heralding in an era of RNomics, and challenging the central dogma. Furthermore, studies are required for understanding the clinical potential of miRNA as therapy tool in oral cancer chemotherapy.

Acknowledgement

Nil.

Financial support and sponsorship

Nil.

Conflict of interest

There are no conflicts of interest.

Ethical policy and institutional review board statement

Not applicable.

Patient declaration consent

Not applicable.

Data availability statement

Data can be available on valid request on contacting to corresponding author mail.

 
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Abstract
Introduction
History
Biogenesis of miRNAs
Mechanism of Gen...
Role in Physiology
Role in Pathology
Significance of ...
Role of miRNA in...
Role of miRNA in...
Circulating miRNAs
Role of miRNA in...
miRNA and Autoim...
Conclusion
References
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