Diagnostic and therapeutic role of microRNAs in oral cancer (Review)
- Authors:
- Published online on: November 13, 2020 https://doi.org/10.3892/or.2020.7854
- Pages: 58-64
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Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Oral cancer is a type of head and neck cancer and its main subtype is oral squamous cell carcinoma (OSCC) (1). OSCC occurs in the oral cavity, which includes the tongue, floor of the mouth, buccal mucosa and alveolar rim (2). OSCC presents a major global health concern, with an estimated >300,000 cases per annum (3) and ~1.8 million deaths (4). Currently, the diagnosis and treatment of OSCC represent a clinical challenge.
miRNAs are a class of small non-coding RNAs that are involved in the regulation of a variety of physiological processes by targeting specific mRNAs (5). miRNAs have been reported to play an important regulatory role in cancer occurrence and progression (6), and they may be of value as targets in oral cancer treatment (7). Due to their stability in human peripheral blood and body fluids and disease-specific expression, an increasing number of studies indicate that miRNAs may represent an ideal set of biomarkers applied in early diagnosis and prognosis of cancers (8).
The focus of the present review was the detailed regulatory role of miRNAs in oral cancer and their value in diagnosis and treatment. The conclusions of this review may contribute to the early diagnosis and targeted therapy of oral cancer.
Expression profile of miRNAs in oral cancer
miRNAs are a family of short, single-stranded, small non-coding RNAs, containing ~20–22 nucleotides (9). The miRNA expression profiles and levels differ between patients with cancer and healthy individuals, and they are implicated in human carcinogenesis (10,11). According to their chemical and structural properties, circulating miRNAs are stable in the serum, plasma and other body fluids (8), and they may be considered as potential clinical diagnostic and prognostic biomarkers.
miRNAs may be novel diagnostic biomarkers in oral cancer
The occurrence of oral cancer is multifactorial, and is accompanied by genetic and epigenetic instability (12). With the widespread application of next-generation sequencing, a growing number of studies have demonstrated that certain miRNAs are differentially expressed in oral cancer. In addition, the results of receiver operating characteristic (ROC) curve and area under the curve (AUC) analysis have indicated that the differentially expressed miRNAs may help distinguish patients with oral cancer from healthy subjects (13,14). As revealed in Table I (13–31), 35 miRNAs were screened, which were reported in the last 5 years with a ROC (AUC) >0.500. For example, Momen-Heravi et al reported that upregulated miR-27b and downregulated miR-136 derived from the saliva were able to differentiate between patients with oral cancer and healthy subjects (15). The ROC (AUC) of miR-21 extracted from oral cytology and miR-99a from the serum were up to 0.910 (16) and 0.911 (17), respectively. Gombos et al reported that miR-155 derived from tissues was able to distinguish between patients with oral cancer and healthy individuals [ROC (AUC)=0.925] (13). These data revealed that miRNAs originating from different samples may be considered as biomarkers for oral cancer diagnosis.
miRNAs as novel prognostic biomarkers in oral cancer
The expression profiles of certain miRNAs have demonstrated a positive correlation with clinical stage, metastasis and patient survival, indicating that these miRNAs may be considered as prognostic indices in oral cancer. Lai et al revealed that dysregulated miR-31-5p expression enhanced OSCC cell migration and invasion and accelerated oral cancer progression (32). In recent years, miRNAs have been reported to be strongly correlated with the survival of oral cancer patients. Chen et al indicated that patients with high expression level of miR-99a displayed a better prognosis and longer overall survival (17). Supic et al revealed that patients with miR-183 overexpression had markedly shorter overall survival and higher risk of poor outcome (23). Zheng et al reported that miR-503-5p, miR-450b-5p, miR-27a-3p, miR-181a-5p and miR-183-5p were overexpressed in patients with oral cancer, and they were all highly associated with cancer cell proliferation, advanced clinical stage and poor prognosis (33). Cheng et al revealed that the expression level of miR-455-5p was associated with the nodal status, stage and overall survival of the patients, suggesting that miR-455-5p may be a promising prognostic marker for predicting the outcome of patients with oral cancer (34). We herein also summarized other miRNAs that may be of prognostic value in oral cancer (Table II). All the aforementioned data indicated that miRNAs may be valuable prognostic indicators in oral cancer.
Therapeutic effects of miRNAs in oral cancer
miRNAs play a key role in regulating the translation or degradation of mRNAs by interacting with the 3′ untranslated region (3′UTR) or coding region of mRNAs and regulating the expression level of their target genes (35). miRNAs are involved in the cellular processes of cancer, such as inflammation, proliferation, stress response, growth, apoptosis, survival and migration (10). Therefore, manipulating miRNA expression in cancer has been attracting increasing attention as a novel therapeutic strategy. It was reported that miR-24-3p, miR-155-5p and miRNA-10a may significantly promote the proliferation of oral cancer cells (18,36,37). These findings suggested that silencing the expression of specific miRNAs may prevent the progression of oral cancer. Conversely, numerous miRNAs have been revealed to have an anticancer function. miR-6887-5p, miR-34a-5p and miR-142-3p markedly suppressed the proliferation of oral cancer cells (38–40). In addition, certain miRNAs, such as miR-204-5p and miR-34a-5p, exert their anticancer effects by inhibiting the aggressiveness and metastasis of oral cancer cells (39,41). The targets and functional roles of miRNAs are listed in Table II (17–19,23,32,33,36–54).
Regulatory mechanism of miRNAs in oral cancer
miRNAs belong to a family of non-coding RNAs that play key roles in suppressing or promoting cancer by interacting with their target mRNAs. Several studies have demonstrated that miRNAs are involved in the occurrence, progression and metastasis of oral cancer (Fig. 1) (53,55).
miRNAs and oral cancer occurrence and progression
Accumulating evidence indicates that miRNAs play a key role in the occurrence and progression of oral cancer. The protein kinase B (AKT) and mammalian target of rapamycin (mTOR) pathways are known to participate in the regulation of oral cancer occurrence (56). Manikandan et al revealed that >40 differentially expressed miRNAs in OSCC may activate the AKT pathway (57). miR-218 can inhibit the activation of mTOR/AKT pathway by targeting Rictor, and then suppress oral carcinogenesis (58). In oral cancer, miR-99 has been revealed to decreased the expression level of mTOR by directly binding with mTOR mRNA, thereby promoting cancer cell growth and increasing tumor size (59,60). The expression level of miR-455-5p has been revealed to be regulated by the TGF-β-dependent pathway, which subsequently promotes oral tumorigenesis by downregulating ubiquitin-conjugating enzyme E2B (UBE2B) (34). Chen et al revealed that CD36 contributed to the proliferation and invasion of OSCC, and miR-1254 may inhibit the progression of OSCC by partially downregulating the expression level of CD36 (61). In addition, inhibiting the expression of miR-423-5p may rescue the carcinogenic effect of lncRNA CASC9 by silencing the expression of SRY-box transcription factor 12 (SOX12) (62). These data revealed that miRNAs participate in oral carcinogenesis and progression by regulating their target genes.
miRNAs and oral cancer cell proliferation and apoptosis
The proliferation and apoptosis of oral cancer cells are regulated by multiple factors, with an increasing number of studies demonstrating that miRNAs are involved in the regulation of these cellular process. Rastogi et al reported that in vitro restoration of miR-377 suppressed OSCC cell growth and induced apoptosis by regulating HDAC9 and its pro-apoptotic target, NR4A1/Nur77 (63). miR-23a-3p may suppress proliferation and promote apoptosis of OSCC cells by targeting fibroblast growth factor 2 (FGF1) (64). By contrast, it was reported that miR-155 contributed to oral cancer cell proliferation, inhibited cell apoptosis and reduced the sensitivity of oral cancer cells to DDP by downregulating Foxo3a expression (65). Furthermore, miR-155 promoted cell cycle progression and cell proliferation and suppressed apoptosis by inhibiting p27Kip1 expression (66).
miRNAs and oral cancer cell migration, invasion and metastasis
The migration, invasion and metastasis of oral cancer cells are highly associated with the therapeutic strategy. miRNAs are involved in the regulation of these processes in oral cancer cells. Fang et al reported that miR-204-5p suppressed oral cancer cell aggressiveness, viability and migration by targeting and inhibiting: Huntingtin-interacting protein 1 (HIP1) expression (41). Overexpression of miR-143 and miR-145 in OSCC cells markedly suppressed the expression of activin A, and suppressed the migration and invasion of oral cancer cells, prevented lymph node metastasis, increased tumor differentiation and prolonged the survival of the patients (67). Huang et al revealed that enhancing the expression of miR-491-5p significantly downregulated the expression of GPCR kinase 2 interacting protein 1 (GIT1), thereby suppressing OSCC cell migration in vitro and lung metastasis in vivo (68). Conversely, overexpression of miR-21 was associated with perineural invasion and worse prognosis in OSCC patients (69). Tu et al reported that overexpression of miR-372 and miR-373 were associated with nodal metastasis, lymph vascular invasion and poor survival by regulating the expression of large tumor suppressor kinase 2 (LATS2) in OSCC cells (70).
miRNAs as novel therapeutic tools in oral cancer
A large volume of evidence has demonstrated that miRNAs play key roles in oral cancer occurrence and growth, cancer cell migration and invasion, cancer progression and patient prognosis. This evidence suggests that miRNAs may be considered as novel therapeutic tools for oral cancer.
It was reported that upregulation of miR-375 markedly inhibited cell proliferation, induced cell cycle arrest in the G0/G1 phase, promoted apoptosis and increased radiosensitivity in OSCC cells, suggesting that miR-375 may be a potential therapeutic target for OSCC patients (71). miR-494-3p was able to enhance the radiosensitivity of OSCC cells by promoting cellular senescence (72). Min et al revealed that overexpression of miR-148a in cancer-associated fibroblasts significantly decreased the migration and invasion abilities of oral cancer cells by directly targeting WNT10B, suggesting that miR-148a may be a novel promising target for the treatment of OSCC (73). Chen et al reported that miR-1254 may inhibit the progression of OSCC, and restoring miR-1254 expression may represent an effective treatment strategy for OSCC (61). Similarly, miR-377 and miR-23a-3p suppressed cell proliferation and promoted apoptosis in OSCC, suggesting that both miR-377 and miR-23a-3p may prove to be of value as therapeutic targets for OSCC in the future (63,64). In summary, all the aforementioned data suggest that miRNAs may be considered as effective anticancer targets, and they may be used to develop novel treatment strategies for oral cancer.
Discussion and outlook
Although great progress has been made in the diagnosis of oral cancer, the methods for early diagnosis and prognosis require further improvements. Early diagnosis may markedly increase the effectiveness of treatment and prolong the survival of patients with oral cancer. Therefore, it is urgent to develop novel biomarkers with higher accuracy, sensitivity and specificity, that are more convenient for clinical detection.
With the development of sequencing technology, an increasing number of miRNAs have been revealed to be specifically expressed in a variety of samples from oral cancer (15,16). These miRNAs also play a key role in regulating cellular processes and behaviors (66,68). miRNAs may represent optimal biomarkers and new therapeutic tools for oral cancer. However, although the miRNAs aforementioned appear to be promising candidates as biomarkers, they require further investigation, including biological study and clinical verification. Furthermore, the source, formation and regulatory networks of miRNAs are quite complex, and the expression level of miRNAs in different stages of oral cancer is also different. Hence, it is necessary to elucidate the mechanism of miRNA formation, which may contribute to early diagnosis, targeted therapy and prognosis evaluation of oral cancer patients. Notably, the therapeutic miRNAs that may be used to develop novel targeted drugs require further research in terms of suitable and effective in vivo delivery methods. Identifying key targets and building a targeted delivery system (such as a nano-miRNA system) will be our future research priorities.
Acknowledgements
Not applicable.
Funding
The present study was supported by the National Science Foundation of China (grant no. 81372908).
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Authors' contributions
JW, RY, JY designed the review and edited the manuscript. JW, NL, XL wrote the manuscript. JW, RY and ZC collected and analyzed data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
OSCC |
oral squamous cell carcinoma |
|
ROC |
receiver operating characteristics |
|
AUC |
area under the curve |
|
mTOR |
mammalian target of rapamycin |
|
AKT |
protein kinase B |
|
UBE2B |
ubiquitin-conjugating enzyme E2B |
|
SOX12 |
SRY-box transcription factor 12 |
|
FGF1 |
fibroblast growth factor 2 |
|
NR4A1/Nur77 |
nuclear receptor subfamily 4 group A member 1 |
|
Foxo3a/p27Kip1 |
forkhead box O3A/cyclin-dependent kinase inhibitor 1B |
|
HIP1 |
Huntingtin-interacting protein 1 |
|
GIT1 |
GPCR kinase 2 interacting protein 1 |
|
LATS2 |
large tumor suppressor kinase 2 |
|
PER1 |
period 1 gene |
|
ACOX1 |
acyl-CoA oxidase 1 |
|
HBp17 |
heparin-binding protein 17 |
|
ARID2 |
AT-rich interaction domain 2 |
|
GLUT1 |
glucose transporter 1 |
|
TMEM182 |
transmembrane protein 182 |
|
CDH1 |
E-cadherin gene 1 |
|
RGMA |
repulsive guidance molecule A |
|
RIG-I |
retinoic acid-inducible gene-I |
|
TNF-α |
tumor necrosis factor-α |
|
RORα |
retinoic acid receptor-related orphan receptor α |
|
BIN1 |
bridging integrator 1 |
|
AXL |
receptor tyrosine kinase |
|
PDCD7 |
programmed cell death 7 |
|
Bmi-1 |
B-cell-specific Moloney murine leukemia virus integration site 1 |
|
BIRC3 |
baculoviral IAP repeat-containing 3 |
|
FAP |
fibroblast activation protein |
|
DENND2D |
differentially expressed in normal cells and neoplasia domain containing 2D |
|
TGFBR1 |
TGF-β receptor 1 |
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