Relevance of micro-RNAs and their targets as a diagnostic and prognostic marker in oral squamous cell carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) ranks sixth among all cancers in the world, affecting various sites of the oral cavity with associated several risk factors. High mortality has been associated with the presence of metastasis during the time of diagnosis and an increase in therapeutic relapses. Micro-RNAs (miRNAs) are a group of small non-coding RNAs with salient roles in the initiation and progression of cancer. The tumorigenesis of OSCC is associated with the dysregulation of several miRNAs. MicroRNAs are an area of recent interest, and numerous studies have been reported and are being undertaken to identify their role in diagnostic and prognostic value for oral cancers. Most of the miRNA processing machinery is considered to be either up-/down-regulated in OSCC, but the underlying mechanism of miRNA dysregulation and their activity as either a tumour suppressor or an oncogene in oral carcinogenesis is not yet clear. The article presents a concise review of the available current literature regarding the various miRNAs' signatures in OSCC and their role as diagnostic/prognostic biomarkers.

INTRODUCTION

Oral squamous cell carcinoma (OSCC) comprises a group of diverse heterogeneous cancers that develop in different oral anatomical locations, associated with several lifestyles and genetic and environmental factors.[1] OSCC accounts for over 40% of head and neck malignancies and is the sixth most common cancer globally.[2] The prevalence of OSCC varies in different areas of Pacific and Asian countries. The majority of the OSCCs get diagnosed at a later stage with tumour node metastasis, resulting in a poor prognosis for the patient.[3] This could be related to their invasive nature despite the advances made in diagnosis and treatment. The 5-year survival rates remain less than 50%, and 35–55% of the patients develop recurrences within 2 years even with advanced therapeutic approaches.[4]

Micro-RNAs (miRNAs or miR) are considered to be the principal regulators of various cellular processes. They are small, single-stranded, and non-coding RNAs (22 nucleotides) that regulate post-transcriptional gene expression.[5] These small molecules were discovered in 1993 in Caenorhabditis elegans.[6] It has been predicted that the human genome encompasses about 1000 microRNA (miRNA) genes,[7] and presently, about 2500 known mature miRNA species are present in the human miR-Base.[8,9] Approximately one-third of human genes might be regulated by miRNAs.[10] Numerous miRNA molecules have been identified to play a key role in a variety of physiologic and pathologic processes and are regarded as critical regulators of gene expression in biological systems.[11]

Over the recent years, miRNAs have been immensely studied and have been identified as the potential biomarkers of cancer. Altered expression of miRNAs has been shown to directly dictate various cancer phenotypes and has been implicated in specific clinical outcomes. It is well established that dysregulation of these RNAs either enhances the expression of oncogenes or subdues the expression of tumour suppressor genes.[12] The expression patterns of miRNAs are associated with cancer growth and expansion and can be considered promising predictive biomarkers in the diagnosis and as therapeutic targets.[13] Several miRNAs have been identified to be differentially expressed in OSCC, indicative of the fact that miRNAs may be involved in the pathophysiology of OSCC. Numerous studies have reported the diagnostic and prognostic significance of miRNA in OSCC, and the purpose of this paper is to investigate the role and relevance of miRNAs as diagnostic biomarkers and their therapeutic potential in OSCC.

miRNA BIOLOGY AND BIOGENESIS

These small RNA molecules have been found to regulate endogenous gene expression through translational repression and messenger RNA cleavage. miRNAs as such do not possess the ability to code proteins but partake in biological processes through their target genes.[14] A single miRNA can target numerous mRNA transcripts, have multiple target sites, and regulate numerous genes downstream.[8]

Several mechanisms are involved in miRNA-mediated post-transcriptional regulation of gene expression: viz. site-specific cleavage, enhanced mRNA degradation, and translational inhibition.[15]

The biogenesis of miRNA follows two mechanisms: canonical and non-canonical pathways wherein the canonical pathway functions as the dominant mechanism.

CANONICAL miRNA BIOGENESIS PATHWAY

miRNA genes are transcribed by RNA polymerase II (Pol II) into primary miRNA (pri-miRNA with a hairpin structure) transcripts within the nucleus. Each miRNA located in the same genomic cluster can be transcribed and regulated independently.[16] This is then subsequently processed in the nucleus and cytoplasm by two endonuclease enzymes: RNA polymerase III: DROSHA and Dicer, respectively. Within the nucleus, miRNA gene transcription is catalysed by the microprocessor complex, comprising the RNase III-type enzyme DROSHA (double-stranded RNA-binding protein [RBP]) and DGCR8 (DiGeorge syndrome critical region 8), resulting in a pre-miRNA sequence of approximately 70–100 nucleotide stem-loop precursor miRNAs/pri-miRNA.[17] The transport of pre-miRNAs from the nucleus to the cytoplasm is aided by Exportin-5. The pre-miRNA is then cleaved by Dicer (cytoplasmic ribonuclease) concurrent with TRBP (HIV-1 TAR RNA RBP) and PACT (protein activator of PKR), adjacent to the TL (apical loop) region liberating the double-stranded/duplex miRNA.[18] The miRNA duplex is then unified with Argonaute (AGO2) protein to form the RNA-induced silencing complex (RISC). After maturation, AGO2 unwinds the miRNA duplex separating the mature RISC complex. This active miRNA–RISC complex binds to target mRNAs.[19] The miRNA targets mRNAs through mRNA cleavage, deadenylation or translational repression [Figure 1: Canonical pathway in the biogenesis of miRNA]. The mature miRNA identifies its complementary sequences and regulates gene expression through binding to 3′-untranslated regions (UTRs) of their target mRNAs which are then degraded or translationally inhibited.

Figure 1.

Canonical pathway in the biogenesis of miRNA

NON-CANONICAL miRNA BIOGENESIS PATHWAY

This pathway uses different combinations of the proteins involved in the canonical pathway; viz. DROSHA, Dicer, exportin 5, and AGO2. Non-canonical miRNA biogenesis is grouped into DROSHA/DGCR8-independent and Dicer-independent pathways. Pre-miRNAs produced by the DROSHA/DGCR8-independent pathway are directly exported to the cytoplasm through exportin 1 without DROSHA cleavage.[20]

In the Dicer-independent pathway, miRNAs are processed by DROSHA from endogenous short hairpin RNA (shRNA) transcripts. The pre-miRNAs are of insufficient length to be Dicer substrates and therefore require AGO2 binding to complete their maturation within the cytoplasm. The entire pre-miRNA is loaded into AGO2 and AGO2-dependent slicing of the 3p strand occurs. Then, the 3-5′ slicing of the 5p strand completes their maturation.[21]

A single miRNA may target up to several hundred mRNAs as high complementarity is not required for regulation, and the resulting aberrant miRNA expression may affect a horde of transcripts, which can influence cancer-related signalling pathways.[22] The potential for miRNA-mediated regulation of gene expression is extensive as 60% of mRNAs are considered to be controlled by miRNAs.

miRNAS IN TUMORIGENESIS AND ITS DETECTION IN CANCERS

miRNA has been an area of interest for a variety of cancers. Literature reports have verified that miRNAs have a critical part in cancer biology either as a tumour suppressor or as oncogenes.[23] The majority of encoding sequences of miRNAs have been located in the cancer-related regions of the genome,[24] and a dysregulated miRNA profile plays an imperative role in tumour-associated bio-pathological processes including initiation, promotion, malignant transformation, progression and metastasis.[25] miRNAs play vital roles in morphogenesis, proliferation, differentiation, apoptosis, metastasis and survival of cancer cells. Many studies have demonstrated that certain cancer has a unique mir signature[11] and has been confirmed to be important diagnostic or prognostic markers in various cancers and serve as targets for novel therapeutic strategies.

Microarray analysis of oligonucleotide miRNA and real-time RT-PCR are the most commonly employed techniques for the assessment of miRNA profiling in a large number of cancer-specific cell types.[26] Next-generation sequencing is emerging as a cost-effective technique for analysis. The materials used for profiling include fresh frozen samples, but recent advancements made it possible to obtain reproducible profiles from formalin-fixed paraffin-embedded tissue (FFPE), thus marking the accessibility of archived tumour tissues for research.[27] In situ hybridisation (ISH) also allows sensitive detection of miRNAs in tissues, defining miRNA cellular localisation.[28] Newer detection methods, to improve the sensitivity and selectivity of miRNA, rely on signal amplification strategies, such as nanoparticle-based amplification, isothermal exponential amplification, rolling circle amplification (RCA), hybridisation chain reaction (HCR) and a combination of these methods.[29]

miRNAs are consistent and demonstrable in body fluids also (plasma and serum) owing to their protection from RNases[30] and many research studies are being carried out for the identification of new biomarkers within body fluids due to their non-invasive nature collection and also on the datum that they reflect the physiological/pathological state.

miRNA dysregulation could initiate tumorigenesis and the oncogenic function of miRNAs vary based on cell or tissue type. Deranged miRNA profiles in cancer cells are tumour-type-specific and related to malignant features.[11]

Several mechanisms have been described for tumorigenesis through miRNA. miRNAs act by inhibiting gene expression with the target mRNAs through direct base-pairing. Overexpression, amplification, and loss of epigenetic silencing of a miRNA-targeting tumour suppressor gene/s could inhibit the activity of an antioncogenic pathway. In contrast, the epigenetic silencing of a miRNA that normally represses the expression of oncogenes might lead to increased protein expression with the gain of oncogenic potency.[31] Any defects in the miRNA processing mechanism can contribute to miRNA-mediated oncogenic processes. Commotion in any of the components that regulate miRNA biogenesis (microprocessor complex, Dicer, AGO2, and GW182) could cause variations in miRNAs, capable of causing cancer.[32]

miRNA AND ORAL SQUAMOUS CELL CARCINOMA

Oral tumorigenesis arises through the accrual of both or either genetic/epigenetic alterations in the expression of coding and non-coding RNAs. Oral cancers express a specific miRNA portfolio, that contributes to maintaining the characteristic epithelial features of the cells.

Numerous studies have analysed miRNA expression profiles in OSCC using microarrays or quantitative reverse transcription-polymerase chain reaction (qRT-PCR). miRNAs that are up- or down-regulated are, respectively, denoted as oncogenic or tumour suppressor miRNAs.

OSCC has been found to be associated with numerous miRNAs. A meta-analysis conducted by Chen et al.[33] found 432 differentially expressed miRNAs in head and neck squamous cell carcinoma (HNSCC). A total of 67 miRNAs with constant directions reported included 46 (68.7%) to be up-regulated and 21 (31.3%) to be down-regulated. Consistency in the regulation pathway was seen in seven miRNAs (miR-21, miR-7, miR-155, miR-130b, miR-31, miR-223 and miR-34b) to be up-regulated and four down-regulated miRNAs (miR-100, miR-99a, miR-125b and miR-375). The other frequently down-regulated miRNA in OSCC reported include miR-133a, −133b, −137 and − 193a.[34]

Among the many reported, miR-21 is broadly studied and may be considered the most striking biomarker for diagnostic, therapeutic and prognostic application.[35] Overexpression of miR-21 and miR-221 and decreased expression of the let-7 family of miRNAs have been frequently detected in OSCC.[36] Increased miR-21 expression in OSCC has been negatively associated with low levels of TPM1 and PTEN – tumour suppressors mediating apoptotic and cell-cycle events, respectively. miR-21 facilitates the growth of OSCC cells, partly through down-regulating TPM1.[37] The miR-221/miR-222 cluster has been depicted to endorse oral carcinogenesis via the downregulation of PTEN.[38]

An inverse relation between let-7b miRNA and Dicer levels has been detected in OSCC cell lines, with elevated levels of Dicer protein inversed with significantly reduced levels of let-7b. Dicer has been associated with cell-cycle regulation and cell growth and is considered a target of let-7 miRNAs. Combined dicer upregulation with let-7b down-regulation yields the progression of OSCC.[39]

Many miRNAs have been found to be site-specific. Decreased levels of miR-138 and miR-222 can enhance and augment the metastatic potential of tongue OSCC.[40]

miRNA as diagnostic biomarkers

Circulating tumoural miRNAs recently have found their way as prospective biomarkers for early detection. Nakamura et al.[10] studied the RNA profiles in ten of the OSCC serum samples via microarrays to identify postulant miRNAs OSCC markers. They identified a panel of six miRNAs as diagnostic markers and found a significant difference in the expression levels of miR-19a, miR-20a, and miR-5100 between OSCC and control groups. miR-19a and miR-20a in OSCC patients were significantly increased, whereas miR-5100 expression was found to be decreased. miR-20a inhibits cancer cell migration, thus, may be considered a prognostic marker.

Liu et al.[41] observed a substantial upregulation in the expression of miR-187-5p in 63 OSCC plasma samples compared to 23 healthy controls. The elevated expression of miR-187-5p was markedly reduced in post-tumour resection samples, suggesting that circulating miR-187-5p originated from the tumour cells and miR-187-5p could act as a potential oncogene, promoting migration and proliferation of oral cancer cells and could be used as a predictor of tumour recurrence.

Elevated serum levels of miR-21 are suggested to have a diagnostic and prognostic value in OSCC. Mahmood et al.[42] observed a significant overexpression of serum miRNA 21 in OSCC samples, compared to controls and also reported its increased expression proportional to tumour size, invasion and metastasis.

miR-196a/b was detected to be up-regulated at the early developmental stages of oral cancer. miR-196a has been considered an excellent marker for detection specificity whereas miR-196b for detection sensitivity[43,44]

Chen Sun and Jianxia Li[45] investigated the role and clinical significance of miRNA-137, a potential marker for the early diagnosis of OSCC. They observed that miRNA-137 showed a decreased expression in OSCC tissues based on the tumour differentiation and exhibited no correlation with the patient's gender/age, TNM stage, habits and lymph node metastasis.

miRNA as prognostic biomarkers

These small RNAs are also considered to be biomarkers for predicting metastasis and survival rates and can be used to differentiate the stages of OSCC tumours. The patterns of expression of various miRNAs have been found to correlate with clinical stage, lymph node metastasis and patient survival. Higher expression of several oncomiRs and lower expression of tumour suppressor miRNAs have been correlated with poor patient outcomes or overall survival. Few oncogenic miRNAs that have been studied as prognostic markers with their targets in OSCC include miR-21 (via Dickkopf-related protein: DKK2), miR-29a (via upregulating MMP2), miR-196 (non-metastatic cells 4 (NME4)), miR-155 (B-cell CLL/lymphoma 6-BCL6), miR-24 (target F-box and WD-40 domain protein 7 (FBXW7)) and miR-1275 (upregulate insulin-like growth factor 1 receptor: IGF-1R and C-C chemokine receptor type 7: CCR7) promote invasion.[46]

Aberrant expression of miR-21 has also been suggested as an independent predictor of poor survival in patients with tongue OSCC.[37] Yoon et al.[47] developed a miRNA-based risk scoring system to identify high-risk early-stage OSCC patients with cancer-specific mortality. They observed that miRNAs-127-3p, 4736 and 655-3p exhibited a prognostic significance related to the AJCC 8 TNM staging system and histologic grading. The high-risk cases showed a 23-fold increased mortality risk with a median time of recurrence of 6 months and a survival time of 11 months. This miRNA scoring system has been evidenced to be reliable for assessing the prognosis of patients with early-stage OSCC.

Serum miR-99a was identified by Chen et al.[48] to be an independent prognostic indicator for OSCC. They observed that patients with high miR-99a expression had longer overall survival and recurrence-free survival.

Supic et al.,[49] in tongue OSCC patients, observed that miR-183 upregulation had shorter overall survival and miR-21 overexpression had a tendency towards poorer survival. miR-1 and miR-133a have been detected at reduced levels in OSCC and mapped to the same chromosomal locus. miR-1 may a play role in the suppression of metastasis by targeting TAGLN2, a gene coding for an actin-binding protein that mediates cell migration and invasion.[50]

The expression of miR-155-5p was found to be elevated in another study carried out in 68 formalin-fixed, paraffin-embedded OSCC specimens, and was found to be associated with higher pathological TNM stage and relapse. miR-155-5p expression was correlated with clinicopathological parameters, angiolymphatic invasion and stage, and it proved to be a prognostic factor for poorer disease-free survival and could be used as a biomarker predicting relapse.[51]

Another study conducted by Liu et al.[52] identified ten miRNAs whose expression levels were highly associated with nodal-disease-free survival, out of which increased expression of miR-21 and miR-107 was found to be commonly associated with OSCC progression and prognosis. They also reported a panel of four miRNA (miR-21-5p, miR-107, miR-1247-3p, and miR-181b-3p) as prognostic biomarkers for nodal disease with high accuracy in assessing the lymph node status.

Rajan et al.[53] elucidated new miRNA prognostic signatures for oral cancer in 30 tumours and 18 normal samples. They observed that the upregulation of miR-196a, miR-21, miR-1237 and downregulation of miR-204, and miR-144 were associated with poor prognosis of OSCC patients and identified that the expression ratio of mir-196a/miR-204 could be used as a predictor for disease recurrence and patient survival.

Considering the varied expression of miRNA, we have investigated the recent research works carried out in miRNA in OSCC as prognostic or diagnostic markers, available in Pub-Med/Medline and Google Scholar databases with the keywords ‘microRNA’ OR ‘miRNA’ AND ‘oral squamous cell carcinoma/OSCC’ AND ‘Prognostic’ OR ‘Diagnostic biomarker’, to retrieve and update related articles published from 2018 to 2022. The abstracts were assessed to validate the relevance of articles with the title of the review. Table 1 lists the biomarkers which have prognostic and diagnostic significance.

Table 1.

MiRNA's as prognostic and diagnostic markers

miRNA	Source	Up/down-regulated	Target	Function	Reference
miR-let-7a	Tissue Cell lines	Down	c-Myc	promotes cell growth and invasion, low expression - poor prognosis	[54]
miR-19a,	Serum	Up	TGFBR3	Marker for OSCC epithelial-to-mesenchymal transition and migration	[10]
miR-20a	Serum	Up	STAT3, PTEN	cell proliferation and cancer progression, prognostic marker	[10]
miR-21	Cell lines	Up	AP1, STAT3	Prognostic tool for survival	[55]
	Plasma	Up		circulating miR-21 originates from tumour mass with a positive association with tumour size, local invasion and metastasis	[42]
miR-23a-3p	Tissue Cell lines	Up	FGF2	suppresses cell proliferation prognostic indicator	[56]
miR-24-3p	Saliva	Up	PER1	Diagnostic biomarker, promotes the proliferation of tumour cells	[57]
miR-29b-1-5p	Tissue Cell lines	Up	CDH1	associated with clinical stage, nodal metastasis, poor prognosis, proliferation	[58]
miR-31-5p	Serum	Up	PTEN/AKT	Diagnostic marker	[59]
miR-99a	Serum	Down	-	Poor differentiation and advanced clinical stage - Prognostic marker	[48]
mir-99b-3p mir-100-5p	Tissue	Up	-	Better survival Poor survival	[60]
miR-105	Tissue Cell lines	Up	-	Promotes Progression of cells	[61]
miRNAs-127-3p, 4736, 655-3p	Tissue	Up		Prognostic marker panel for early-stage OSCC	[47]
miR-134	Plasma Saliva	Up	PDCD7 (Programmed Cell Death 7)	Diagnostic marker	[62]
miRNA-137	Tissues Cell lines	Down		Early diagnosis	[45]
miR-139-5p	Tissue Cell lines	Down	CXCR4	poor survival in OSCC	[63]
microRNA-149-3p	Tissue Cell lines	Down	MMP2	Inhibit OSCC cell migration, prognostic biomarker and therapeutic target for OSCC	[64]
miR-155-5p	Tissue	Up	ARID2	proliferation, migration, invasion, EMT of OSCC cells, prognostic marker	[51,65]
miR-183	Tissues	Up		potential marker of clinical stage, a prognostic biomarker of tumour progression	[66]
miR-196a miR-196b	Tissues Cell lines	Up		Low expression - favourable Prognostic marker	[44]
miR-200b-3p	Plasma	Up		Diagnostic biomarker	[67]
miR-204	Tissue	Down	CDC42, RAB22A, EZR	Patient survival, prognostic marker	[53]
miR-222	Tissue Cell lines	Up	CDKN1B	Early diagnostic marker	[68]
miR-423-5p	Saliva	Up	-	OSCC progression and metastasis - diagnostic and prognostic biomarker	[69]
miR-448	Tissue	Up	MPPED2	prognostic marker	[70]
miR-626 miR-5100	Serum	Up	-	Prognostic role, a predictor of survival	[71]
miR-654-5p	Tissue Cell lines	Up	GRAP	promote proliferation, metastasis, chemoresistance of OSCC, diagnostic marker	[72]
MiR-770	Tissue Cell lines	Up	Sirtuin 7 (Sirt7)	promoted OSCC cell migration and invasion, metastasis, poor patient survival	[73]
MiR-4282	Cell lines	Down	LIN28B	inhibits tumour progression, prognostic significance	[74]
miR6870-5p miR7111-5p	Tissue	Down	SRF	prognostic marker, Early detection of OSCC	[75]

miRNA as a target for OSCC therapy

Resistance to chemotherapy and radiotherapy are the major challenges faced in the management of OSCC patients as a high proportion of OSCC lesions fail to respond to these treatment modalities. miRNA-based cancer therapy has shown a promising future, as they have the ability to simultaneously target multiple effectors of pathways involved in cell proliferation, differentiation and survival.

miR-101 functions as a tumour suppressor in OSCC by hindering tumour cell proliferation and inducing apoptosis by targeting TGF-βR1. Wang et al.[76] observed that miR-101 levels were down-regulated in OSCC cell lines and tissues, repressing cell proliferation and with reduced OSCC growth and metastasis. miR-101could act as a therapeutic agent.

Kang et al.[77] studied the effect of miR198 on cell proliferation and invasion through direct targeting of cyclin-dependent kinase 4 (CDK4). The overexpression of miR-198 was observed to suppress tumour growth and metastasis in OSCC cells and miR-198/CDK4 axis may be considered as a therapeutic target in OSCC.

miRNAs have been increasingly targeted for therapeutic purposes as they can be effectively administered through local and systemic delivery of miRNA inhibitors (anti-miRNA oligonucleotides or miRNA sponges. Ogawa et al.[78] identified a locked nucleic acid (LNA)/DNA antisense oligonucleotide against miR-361-3p (LNA-miR-361-3p) which showed a high degree of growth inhibition of OSCC cell lines and miRNA-361-3p can be considered as a potential therapeutic target for oral squamous cell carcinoma.

Zheng et al.[79] observed that miR-211 was highly expressed in OSCC tissues and cell lines, and via its potential target BIN1 (bridging integrator-1), it could inhibit the proliferation, migration and invasion abilities of OSCC cells. They also found that the miR-211 inhibitor could decrease the tumorigenic behaviour of OSCC cells by upregulating BIN1 expression and inhibiting the activation of the EGFR/MAPK pathway, thereby evidencing that miR-211 could function as a potential therapeutic target for the OSCC treatment.

miR-18a-5p/Smad2 could prove to be a potential therapeutic target for OSCC.[80] The overexpression of miR-18a-5p could decrease cell viability, migration and the invasion abilities of OSCC cells and inhibit cell apoptosis.

miRNA IN DIAGNOSTICS AND ITS FUTURE DIRECTIONS IN CANCER DIAGNOSIS AND THERAPY

The literature has evidenced the potential of miRNAs as a diagnostic tumour marker and their expression patterns have been linked to clinical outcomes such that miRNAs modulate tumour behaviour, tumour progression and metastasis.[81]

Many studies have reported the role of miRNAs in many oncogenic processes and the feasibility of miRNA-based therapies. Therapeutic miRNA methods are based on miRNA mimics (miRNA-replacement therapy) and anti-miRs (miRNA-silencing therapy). Based on their role, miRNAs can be either silenced with miRNA inhibitors or therapeutically administered into tumour cells via vectors or through direct delivery into the tissues.[82] Oncogenic miRNAs can be silenced using anti-miR oligonucleotides, miRNA sponges, miRNA masking, and small RNA inhibitors.[83] Li et al. have demonstrated that intravenous injection of antisense miR-21 oligonucleotides into tongue squamous cell carcinoma murine models have been shown to reduce tumour growth.[37] The miRNA sponge method is based on transcripts with multiple complementary binding sites to specific miRNAs, thereby making enabling it to inhibit an entire family of related miRNAs.[84] The ‘SMIR-approach’/inhibitory-miRNA therapy is based on small-molecule inhibitors of miRNAs that are known to interact with RNA, inhibiting miRNA biogenesis or hindering miRNA-target interaction.[85] Wong et al.[86] established that miR-184 inhibitor reduced the proliferation rate in three different tongue squamous cell carcinoma cell lines.

Many studies have also validated the role of miRNAs in chemosensitivity and drug resistance for OSCC. The role of miR-23a and miR-214 in chemoresistance and miR-21 in chemosensitivity have been demonstrated by the administration of anti-miR-23a, anti-miR-214, or pre-miR-21 plasmid in the Tca/cisplatin line which reduced the cell viability during cisplatin treatment.[87]

miRNAs are being used in nanotherapeutics for the treatment of cancer. The co-delivery of an anti-miRNA with a chemotherapeutic drug holds the potential as an improved treatment modality. These molecules have a synergistic effect in combinational therapy. Targeted delivery of short RNA therapeutics in combination with chemotherapeutic drugs not only increases its uptake by cancer cells but also inhibits chemoresistance in cancer cells, thereby enhancing their cytotoxic effects.[88]

CONCLUSION

The repository of miRNAs associated with OSCC is ever-increasing. Many studies are ongoing, and there exist numerous unknown and unidentified miRNAs that play a pivotal role in regulating the hallmarks of tumorigenesis. The use of miRNA as biomarkers for the diagnosis of OSCC has been promising, but there still exists a need for further understanding of miRNA biology in OSCC. It is highly necessary to further assess the different roles of miRNAs, which can contribute to early diagnosis, targeted therapy, and prognostic evaluation of oral cancer patients. To determine the clinical value of miRNA expression, the classification of OSCC by site specificity and therapeutic outcome is a rational strategy to pursue and the biggest challenges for the future will be the creation of cancer-specific miRNA signature panels that can be highly reproducible and independently predictive of clinico-biological features of the tumour to improve diagnosis and treatment. A combination of several miRNAs would also contribute to the development of multi-omic panels for refining precision oncology. With the existing robust technology and high-end bioinformatics, validating the panel of miRNAs associated with OSCC holds a promising avenue for changing its prognosis and improving its clinical outcome.

Author contribution statement

Priya Thomas undertook literature mining and drafted the manuscript, K Auxzilia Preethi and Sushmaa Chandralekha Selvakumar helped with literature mining and revision. Prathiba Ramani helped in the critical review of the manuscript and Durairaj Sekar was responsible for the final validation and proofreading of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.