miRNA Expression in Oral Squamous Cell Carcinoma: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Iphigenia Gintoni
,
Stavros Vassiliou
,
George P. Chrousos
,
Christos Yapijakis

Oral squamous cell carcinoma (OSCC) is one of the most prevalent human malignancies and a global health concern with a poor prognosis despite some therapeutic advances, highlighting the need for a better understanding of its molecular etiology. The genomic landscape of OSCC is well-established and recent research has focused on miRNAs, which regulate gene expression and may be useful non-invasive biomarkers or therapeutic targets. A plethora of findings regarding miRNA expression have been generated, posing challenges for the interpretation and identification of disease-specific molecules. In order to identify the most important regulatory miRNAs, genetics and epigenetics were bridged for the first time, focusing on the key genes implicated in OSCC development. Based on published reports,  custom panels of fifteen major oncogenes and five major tumor suppressor genes have been developed. Following a miRNA/target gene interaction analysis and a comprehensive study of the literature,   the miRNA molecules which target the majority of these panels were selected among all those reported to be downregulated or upregulated in OSCC, respectively. As a result, miR-34a-5p, miR-155-5p, miR-124-3p, miR-1-3p, and miR-16-5p appeared to be the most OSCC-specific.

  • OSCC
  • oral cancer
  • genes
  • mutations
  • miRNA

1. Introduction

The oral cavity is the most prevalent site for malignancies of the gastrointestinal and upper respiratory tracts [1]. Characterized by the uncontrolled growth of abnormal cells in the oral cavity, including the lips, tongue, gums, and lining of the cheeks, oral cancer is one of the most common human malignancies, ranking sixth in prevalence worldwide with an estimated global incidence of more than 377,700 new cases in 2020 [2]. More than 95% of diagnosed oral cancer cases are represented by oral squamous cell carcinoma (OSCC), which arises from the stratified squamous epithelial layer of the oral mucosa [3][4]. OSCC is a significant global health concern, with alarming mortality rates of more than 60% [5], largely due to the fact that over 50% of patients are diagnosed in advanced stages (III and IV) and exhibit lymph node infiltration [5][6][7]. Consequently, despite advances in therapeutic approaches such as chemotherapy, radiation, and surgical excision, OSCC mortality rates have remained exceptionally high for a minimum of two decades [8]. Recurrence rates of OSCC are also high, with up to 45% of patients relapsing and facing survival odds of less than 10% [9][10], highlighting the need for further understanding of OSCC as a complex and heterogeneous disease involving the well-established dysregulation of multiple genes and several, currently explored, epigenetic signatures [11][12]. In accordance with other malignancies, OSCC is characterized by the pathological dysregulation of the cell cycle [13]. Although its genetic landscape can be diverse, several genes stand out, demonstrating unique mutational patterns, while others are reported to exhibit characteristically abnormal expression levels within the tumor’s microenvironment [14].
Beyond genetics, the role of epigenetic alterations to OSCC has been under investigation in recent years, with a particular focus on microRNAs (miRNAs), a class of small non-coding RNAs that have emerged as essential regulators in OSCC development and progression. MiRNAs regulate post-transcriptional gene expression by binding to the 3’ untranslated regions (UTRs) of target messenger RNAs (mRNAs), causing their degradation or translational suppression [15]. MiRNAs are significantly overexpressed or downregulated in malignant tissues compared to normal tissues, presenting as tumor-suppressing or oncogenic or epigenetic factors (oncomiRs), depending on whether they inhibit oncogene or tumor-suppressor gene expression [16].
MiRNA dysregulation has been identified in OSCC, leading to abnormal gene expression patterns that are associated with oral carcinogenesis. Numerous studies have revealed multiple miRNAs that are involved in essential biological processes such as cell proliferation, apoptosis, invasion, metastasis, and angiogenesis [17]. Although genetic and epigenetic mechanisms were initially thought to be discrete, it is now known that they present a strong interdependent relationship, which, if decoded, could fill the gaps and assist in mapping the overall molecular signatures of OSCC, resulting in a better understanding of its etiology, decidedly reliable biomarkers or even targeted epigenetic therapeutics [12].

2. MiR-155-5p in OSCC

2.1. Expression Patterns in OSCC

MiR-155-5p is significantly overexpressed in OSCC tissues relative to adjacent healthy margins (p < 0.0001) and is highly upregulated in HPV-positive compared to HPV-negative tumors, functioning as a marker useful for distinguishing HPV-induced tumors [18]. In OSCC cell lines, there is a significant correlation between heightened levels of miR-155-5p in OSCC cell lines and a notable augmentation in OSCC cell proliferation, colony formation, as well as enhanced invasive and migratory capabilities. Conversely, the suppression of miR-155-5p yields contrasting outcomes [19].
The upregulation of miR-155-5p in OSCC tissues and cell lines has been found to exhibit a significant association with aggressive characteristics, including larger tumor size, advanced stage and grade, lymph node metastasis facilitated by EMT induction, reduced disease-free survival, and unfavorable overall survival, thus highlighting its potential not only as a diagnostic but also as a prognostic tool [19][20][21]. Moreover, there seems to be a positive correlation between elevated levels of miR-155-5p and the emergence of resistance towards the chemotherapeutic agents 5-FU (5-Fluorouracil) and cisplatin, which are commonly employed in the treatment of OSCC [20][22].

2.2. Known Target Genes and Affected Pathways

The main target of miR-155 is the FoxO3a member of the FOXO family of transcription factors, which regulates multiple tumor suppressor genes via the FOXO signaling pathway. Consequently, overexpression of miR-155-5p may disrupt the FOXO-induced immunological and cell-cycle regulation. In addition, miR-155-5p harbors targets that are involved in the b-glycal biosynthesis pathway, which is essential for OSCC progression and lymph node metastasis, in which increased glycosylation of molecules such as adhesion-related proteins takes place [18][23]. In addition, by directly targeting the 3′UTR of its mRNA transcript, miR-155-5p inhibits the expression of ARID2 and is responsible for a substantial decrease in its levels in OSCC. Inhibition of ARID2 expression by miR-155-5p results in a rise in high levels of E-cadherin, vimentin, and snail proteins, indicating that the miR-155-5p/ARID2 axis is essential for promoting tumor growth and mediating OSCC-related EMT and subsequent metastasis [19][24].
Furthermore, the expression of TP53INP1 and, consequently, its mRNA and protein levels are also downregulated in light of miR-155-5p overexpression in OSCC. TP53INP1 is a well-known tumor suppressor that regulates apoptosis, cell-cycle arrest, and cell migration. The targeting of miR-155-5p has been proposed as a useful treatment strategy aimed at improving the efficacy of OSCC-targeting chemotherapy [25]. Another known target gene of miR-155-5p is CDKN1B which regulates 27Kip1 cyclin-dependent kinase inhibitor, which mediates the cell cycle progression at phase G1, and its degradation is required for cell proliferation to occur. While the upregulation of 27Kip1 exerts apoptotic and anticancerous effects, its downregulation has been associated with the progression of numerous neoplasms. In the case of OSCC, the typical upregulation of miR-155-5p reduces p27Kip1 levels, thereby promoting proliferation and oncogenesis, whereas the suppression of miR-155-5p results in the upregulation of p27Kip1 expression, which reduces proliferation and inhibits tumorigenicity [23]. Finally, miR-155-5p has been shown to induce oncogenesis in OSCC by suppressing the expression of CDC73 (parafibromin), a key tumor suppressor, thereby inhibiting apoptosis and promoting growth while simultaneously inducing inflammation by suppressing the expression of SOCS1, a well-known anti-inflammatory factor [20][26].

3. MiR-16-5p in OSCC

3.1. Expession Patterns in OSCC

It has been reported that miR-16-5p, also known as miR-16, fulfills a tumor suppressor role in OSCC by inducing apoptosis of malignant cells and inhibiting tumor growth [23][27]. Compared to normal specimens and tumor-free adjacent tissues, OSCC tumors and cell lines exhibit significantly lower expression of miR-16, and it has been shown to be especially downregulated in higher-grade lesions, thus serving as a potential non-invasive tool for OSCC diagnosis and distinguishing advanced tumors [23][27][28][29]. It has been reported that miR-16 is downregulated in approximately 60% of OSCC tumors [30], and it has been strongly correlated with lower disease-free and overall survival rates of patients, highlighting its potential as a prognostic marker [27][31].
The introduction of miR-16-mimicking molecules into OSCC cell lines results in the inhibition of proliferation and robust apoptotic effects, whereas the inhibition and silencing of miR-16 has the exact opposite effect [29]. The quantification of miR-16 in plasma samples from OSCC patients yielded results opposite to those obtained from tissue. In fact, miR-16 levels were higher in plasma samples, which was attributed to the selective release of tumor-suppressing miRNAs by OSCC cells [32].

3.2. Known Target Genes and Affected Pathways

MiR-16 acts as a tumor suppressor by decreasing the expression levels of genes that encode factors involved in the PI3K/Akt signaling pathway, such as BCL2, MTOR, CCND1, CCND3, SGK3, and AKT3, which are implicated in cell cycle progression and cell survival, as well as growth and proliferation thus outlining its tumor suppressing, pro-apoptotic role both in vivo and in vitro. Nonetheless, in the typical case of miR-16-5p downregulation, PI3K/Akt oncogenic signaling may be amplified and overactivated, resulting in tumor growth and disease progression [23][32]. AKT3, as well as BCL2-like protein 2 (BCL2L2), are highly expressed in OSCC tissues and cell lines, which exhibit significantly low expression of miR-16, whereas the induced higher expression of miR-16 and the decrease in their protein levels were successful in reducing OSCC proliferation and tumor size [29].
In addition, miR-16 exerts its tumor-suppressing properties by directly targeting the 3′UTR of the mRNA encoding the Tousled-Like Kinase 1 (TLK1), thereby inhibiting its expression. TLK1 interacts strongly with the AKT-interacting protein (AKTIP), and its elevation leads to the overactivation of the PI3K/AKT pathway, which has been identified as a key driver in numerous malignancies, including OSCC [27][33]. In OSCCs with substantially downregulated expression of miR-16-5p, the expression of TLK1 is significantly elevated compared to adjacent normal tissues, indicating its subsequent dysregulation due to miR-16 suppression [27]. Finally, miR-16 inhibits tumor growth in OSCC and induces apoptosis in vivo and in vitro by inhibiting the Wnt/β-catenin signaling pathway, which is highly upregulated in OSCC and accounts for cell fate, proliferation, and migration. Therefore, the induced overexpression of miR-16 has been proposed as a potential alternative treatment for OSCC [34].

4. MiR-1-3p in OSCC

4.1. Expression Patterns in OSCC

MiR-1-3p, also referred to as miR-1, is recognized as a tumor suppressor miRNA in OSCC. It plays a pivotal role in promoting apoptosis and inhibiting the migration and invasiveness of tumor cells [23][35]. Conversely, the downregulation of miR-1 leads to the activation of these properties, along with enhanced colony formation in OSCC cell lines [23][26][35]. In OSCC tumors, it is commonly observed that the expression levels of miR-1-3p are markedly diminished. This reduction in miR-1-3p levels has been found to facilitate cancer cell migration and stimulate invasion by activating the process of EMT. This finding elucidates a significant correlation between the notably diminished expression of miR-1 and the occurrence of lymph node metastasis, advanced tumor stages (III and IV), as well as a generally inferior prognosis [17][28][35][36]. In contrast, the upregulation of miR-1 through induction has been shown to possess therapeutic promise in the context of OSCC by effectively suppressing the proliferation and migration of malignant cells [35][36].

4.2. Known Target Genes and Affected Pathways

MiR-1 normally suppresses migration and invasion by negatively regulating the expression of Slug or SNAI2 (snail family transcriptional repressor 2), a crucial EMT regulator, by targeting the 3′UTR of its mRNA. In the typical case of miR-1-3p downregulation in OSCC, Slug is overexpressed, resulting in the diminishment of E-cadherin expression, thus promoting EMT and bestowing invasion dynamics to OSCC cells [35].
The EGFR gene, which exhibits notably elevated expression in OSCC cells, is identified as an additional direct target of miR-1, further supporting its role in tumor suppression. The downregulation of EGFR expression and signaling has been observed in cases where miR-1 overexpression is induced. This downregulation leads to a decrease in the aggressiveness of OSCC and suggests that miR-1 might serve as a potential therapeutic agent [35][37]. The c-MET gene, which encodes a tyrosine kinase that plays a role in cellular proliferation, migration, and invasion, has been identified as a direct target of the tumor suppressor miR-1-3p [37][38]. The expression of c-MET is observed to be markedly elevated in head and neck SCC, which may be attributed to the substantial decrease in the expression levels of its regulatory molecule miR-1-3p, thus contributing to the activation of oncogenic signaling pathways [37].
Alongside normally regulating migration and invasion, miR-1-3p also inhibits OSCC proliferation by suppressing the expression of the DKK1 (dickkopf WNT signaling pathway inhibitor 1) gene of the WNT signaling pathway, that is typically overexpressed in various cancers, including OSCC tissues and cell lines, and stimulates proliferation, migration, and invasion. Introducing a miR-1-3p mimic to OSCC cell lines leads to the suppression of migratory and invasive dynamics and to declined proliferation by inducing the suppression of DKK1 expression levels [36].

5. MiR-124-3p in OSCC

5.1. Expression Patterns in OSCC

MiR-124-3p, also referred to as miR-24, is recognized as a tumor suppressor miRNA in a number of cancers, including OSCC. It possesses the capacity to impede the adhesion and movement of malignant cells, induce programmed cell death, and hinder tumor growth [28][39][40]. The expression levels of miR-124-3p have been observed to exhibit a notable downregulation in both tissue and saliva samples obtained from patients diagnosed with OSCC [28][39][41]. Additionally, animal models of OSCC have demonstrated a similar decrease in miR-124-3p levels within tumor cells [42]. Upregulation of miR-124-3p in OSCC cell lines has been shown to be a robust indication of its ability to suppress tumor growth through the inhibition of cancer cell migration and invasion [40].
The downregulation of miR-124-3p is a distinguishing feature observed in SCCs affecting the oropharynx and oral cavity. Conversely, it has been documented to be upregulated in SCCs affecting the larynx and pharynx. In addition, the expression patterns of miR-124-3p have the potential to be utilized in distinguishing between HPV-positive and HPV-negative OSCCs. This is due to its notably reduced expression in the presence of HPV, while it is upregulated in HPV-free tumors. In addition, it is worth noting that miR-124-3p may potentially function as a molecular marker for staging OSCC. This is supported by the significant downregulation of miR-124 in stage IV OSCCs, as opposed to the upregulation observed in stages II and III [41]. In addition, the large downregulation of miR-124-3p has been observed to confer resistance to cisplatin, thereby posing a significant challenge to the efficacy of therapeutic interventions against OSCC [43].

5.2. Known Target Genes and Affected Pathways

MiR-124 has been documented to selectively target multiple genes that have been implicated in the development and progression of malignancies, thereby exerting its suppressive effects on tumor growth. However, these tumor suppressive effects are compromised when miR-124 is downregulated in OSCC [40][42][43][44]. MiR-124 is reported to exert a suppressive effect on OSCC motility. This is achieved through the targeting of the mRNA of the ITGB1 gene, which encodes the integrin subunit β 1 (ITGB1). The ITGB1 protein is known to play a crucial role in the oncogenic PI3K/AKT cascade. MiR-124 typically decreases the levels of ITGB1 protein and mRNA expression in OSCC cells through its interaction with two conserved binding sites located in the 3′UTR of its mRNA. The results of miR-124 in OSCC cells support its tumor-suppressive role. This is evidenced by the significant decrease in ITGB1 expression within OSCC cells following miR-124-induced overexpression. Additionally, miR-124 intervention leads to the inhibition of OSCC cell adherence and motility. These findings suggest that dysregulation of miR-124 may play a critical role in promoting the progression of OSCC [40].
The gene encoding CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), is another target of miR-124-3p that is highly correlated with cancer cell migration and overall malignant progression in general. CCL2 is frequently upregulated in OSCC tissues and is also observed to be overexpressed in plasma samples of OSCC patients. The overexpression of CCL2 has been found to facilitate tumor progression by attracting immune cells to the tumor microenvironment, with the ability to secrete a diverse array of growth factors and cytokines, thereby augmenting both the growth and invasion capabilities of the malignancy. The observed decrease in expression of miR-124-3p, leading to its diminished tumor-suppressive function, may provide a potential explanation for the observed increase in CCL2 levels [42][44]. Finally, it is indicated that miR-124 suppresses the expression of TRIM14 (Tripartite Motif Containing 14) by interacting with the 3′UTR of its mRNA. The dysregulation of TRIM14 has been observed in various malignancies and has been shown to facilitate cell proliferation and inhibit apoptosis in colorectal cancer by suppressing the PTEN tumor suppressor [43][45]. The upregulation of TRIM14 expression, potentially caused by the downregulation of miR-124, has been documented as a contributing factor in the development of tongue OSCC. Additionally, this upregulation has been found to confer chemoresistance to cisplatin, a commonly used treatment for OSCC. In accordance with the above, the overexpression of miR-124 is observed to significantly downregulate TRIM14 levels while also reducing cisplatin resistance in tongue OSCC [43].

6. MiR-34a-5p in OSCC

6.1. Expression Patterns in OSCC

MiR-34a-5p, alternatively referred to as miR-34a, has been identified as a well-established tumor suppressor in various types of cancer [46]. In regards to OSCC, research has predominately revealed a major decline in the levels of miR-34a-5p in OSCC tumor specimens and OSCC cells when compared to normal tissues and cell lines. This reduction has exhibited a strong association with more aggressive phenotypes, as well as with lymph node metastasis and unfavorable overall prognosis among OSCC patients [47][48][49]. In contrast, the exogenous stimulation of miR-34a in OSCC cell lines leads to the inhibition of EMT and a notable reduction in the cells’ ability to invade and migrate. In addition, the overexpression of miR-34a causes the arrest of cells in the G1 phase of the cell cycle, thereby inhibiting the growth and proliferation of OSCC. This highlights the tumor-suppressive function of miR-34a, as it not only hinders tumor growth but also provides protection against cell migration and metastasis [49].
The downregulation of miR-34a is observed in precancerous oral conditions as well. This is evidenced by the significantly reduced levels of miR-34a in saliva samples obtained from patients with leukoplakia compared to samples from corresponding healthy controls. These findings highlight the potential implications of miR-34a in the early stages of oral oncogenesis, as well as into malignant transformation [47]. In addition, it has been observed that the expression levels of miR-34a-5p are markedly reduced in exosomes originating from cancer-associated fibroblasts (CAFs) in OSCC. CAFs play a critical role in promoting malignant progression by releasing exosomes that contain various epigenetic factors, particularly miRNA molecules, which are acquired from neighboring cells. The observed decrease in the expression of miR-34a in OSCC CAFs has been found to be strongly associated with increased cell proliferation and a notable rise in the metastatic capacity of the malignant tumor. In contrast, the upregulation of miR-34a-5p in OSCC CAFs exhibits contrasting outcomes, as it inhibits the progression of OSCC and modulates the tumor’s malignant behavior [50].
Contrary to prevailing consensus, a subset of studies has characterized miR-34a as an oncomiR in OSCC, positing its involvement in the pathogenesis and progression of the neoplasm through the facilitation of malignant proliferation [47]. However, these findings have stimulated ongoing debate and controversy. Indeed, a number of studies have demonstrated that miR-34a exhibits increased expression in OSCC tissues in comparison to normal oral specimens. Additionally, elevated levels of the miRNA have been detected in saliva samples from individuals diagnosed with OSCC, leading to its potential application as a non-invasive method for detecting OSCC and aiding in the early diagnosis of cancerous lesions [28][47]. Pertaining to miRNA expression patterns in head and neck SCCs, overexpression of miR-34a has been primarily reported in tissue specimens of laryngeal cancer, as opposed to oral cancerous tissues. However, miR-34a-5p upregulation in both OSCC and laryngeal cancer specimens has been correlated with a better prognosis and lower mortality rates. This further emphasizes the protective effects of miR-34a-5p rather than its oncogenic potential [51].

6.2. Known Target Genes and Affected Pathways

Interleukin 6 receptor (IL6R), which activates the oncogenic STAT3 transcription factor, is a verified direct target of miR-34a that interacts with the 3′UTR of its mRNA [49][52]. It is demonstrated that miR-34a is capable of modulating the intrinsic expression of IL6R in OSCC cells. This is supported by the observation that the mRNA levels of IL6R are significantly decreased in cell lines where miR-34a overexpression has been exogenously induced. In contrast, it has been reported that OSCC cells with diminished expression of miR-34a demonstrate significant upregulation of the receptor. The upregulation of miR-34a leads to the downregulation of the IL6/STAT3 signaling pathway, primarily mediated by IL6R. Both IL6R and STAT3 levels experience a substantial reduction when miR-34a is upregulated. It is hypothesized that this phenomenon is one of the underlying mechanisms through which miR-34a suppresses proliferation and metastasis. Consequently, the overexpression of miR-34a has been suggested as a potentially effective therapeutic strategy for combating OSCC. The downregulation of miR-34a in OSCC has been observed to have contrasting effects, potentially leading to an upregulation of IL6/STAT3 oncogenic signaling. This, in turn, may contribute to the exacerbation of malignant progression and metastasis in OSCC [49].
Matrix Metalloproteases 9 and 14 (MMP9, MMP14), the expression of which is known to be significantly upregulated in all cancer types, are two additional validated target genes of miR-34a, with binding sites lying on the 3′UTRs of their mRNAs [46][53]. The levels of endogenous proteins MMP9 and MMP14 were found to be significantly decreased due to the overexpression of miR-34a in tongue OSCC cell lines. This reduction in protein levels was also observed to be associated with the inhibition of invasion and migration. In contrast, when miR-34a was suppressed, the expression levels of both metalloproteases exhibited significant increases [46][48]. Furthermore, there are reports indicating that miR-34a-5p plays a role in regulating the expression levels of its direct target gene AXL, with the aim of inhibiting the proliferation and metastasis of OSCC. The activation of AXL signaling has been linked to increased survival, proliferation, migration, and invasion of cancer cells [50][54]. In the context of OSCC, the overexpression of AXL has been associated with elevated rates of proliferation and migration. This may be attributed to the downregulation of miR-34a, a frequent finding in OSCC, which promotes tumor progression, EMT, and metastasis. These effects are mediated through the overactivation of the AKT/GSK-3β/β-catenin/Snail signaling pathway. Consequently, this pathway upregulates the expression of MMP2 and MMP9, leading to increased aggressiveness and disease progression in OSCC [50].
Finally, the SATB2 (special AT-rich binding protein-2) oncogene, known for its significant involvement in cancer development, is directly targeted by miR-34a. The downregulation of the miR-34a/SATB2 axis has a significant functional impact on the growth, invasion, and migration of OSCC cells. In particular, it was observed that OSCC tissues with reduced levels of miR-34a demonstrate a significant increase in the expression of SATB2. On the contrary, the overexpression of miR-34a had a tumor-suppressive effect by causing a notable decrease in SATB2 expression, thereby inhibiting the proliferation, invasion, and migration associated with OSCC [55][56].

This entry is adapted from the peer-reviewed paper 10.3390/genes14081578

References

  1. Pare, A.; Joly, A. Oral cancer: Risk factors and management. Presse Medicale 2017, 46, 320–330.
  2. Ali, K. Oral cancer—The fight must go on against all odds. Evid.-Based Dent. 2022, 23, 4–5.
  3. Johnson, D.E.; Burtness, B.; Leemans, C.R.; Lui, V.W.Y.; Bauman, J.E.; Grandis, J.R. Head and neck squamous cell carcinoma. Nat. Rev. Dis. Primers 2020, 6, 92.
  4. Bugshan, A.; Farooq, I. Oral squamous cell carcinoma: Metastasis, potentially associated malignant disorders, etiology and recent advancements in diagnosis. F1000Research 2020, 9, 229.
  5. Abati, S.; Bramati, C.; Bondi, S.; Lissoni, A.; Trimarchi, M. Oral Cancer and Precancer: A Narrative Review on the Relevance of Early Diagnosis. Int. J. Environ. Res. Public Health 2020, 17, 9160.
  6. Li, L.; Li, C.; Wang, S.; Wang, Z.; Jiang, J.; Wang, W.; Li, X.; Chen, J.; Liu, K.; Li, C.; et al. Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype. Cancer Res. 2016, 76, 1770–1780.
  7. Gharat, S.A.; Momin, M.; Bhavsar, C. Oral Squamous Cell Carcinoma: Current Treatment Strategies and Nanotechnology-Based Approaches for Prevention and Therapy. Crit. Rev. Ther. Drug Carr. Syst. 2016, 33, 363–400.
  8. Khurshid, Z.; Zafar, M.S.; Khan, R.S.; Najeeb, S.; Slowey, P.D.; Rehman, I.U. Role of Salivary Biomarkers in Oral Cancer Detection. Adv. Clin. Chem. 2018, 86, 23–70.
  9. Ghantous, Y.; Bahouth, Z.; Abu El-Naaj, I. Clinical and genetic signatures of local recurrence in oral squamous cell carcinoma. Arch. Oral Biol. 2018, 95, 141–148.
  10. Weckx, A.; Riekert, M.; Grandoch, A.; Schick, V.; Zoller, J.E.; Kreppel, M. Time to recurrence and patient survival in recurrent oral squamous cell carcinoma. Oral Oncol. 2019, 94, 8–13.
  11. Fantozzi, P.J.; Bavarian, R.; Tamayo, I.; Bind, M.A.; Woo, S.B.; Villa, A. The role of family history of Cancer in Oral Cavity Cancer. Head Face Med. 2021, 17, 48.
  12. Vatsa, P.P.; Jindal, Y.; Bhadwalkar, J.; Chamoli, A.; Upadhyay, V.; Mandoli, A. Role of epigenetics in OSCC: An understanding above genetics. Med. Oncol. 2023, 40, 122.
  13. Sasahira, T.; Kirita, T. Hallmarks of Cancer-Related Newly Prognostic Factors of Oral Squamous Cell Carcinoma. Int. J. Mol. Sci. 2018, 19, 2413.
  14. Deshmukh, A.; Rao, K.N.; Arora, R.D.; Nagarkar, N.M.; Singh, A.; Shetty, O.S. Molecular Insights into Oral Malignancy. Indian J. Surg. Oncol. 2022, 13, 267–280.
  15. Yapijakis, C. Regulatory Role of MicroRNAs in Brain Development and Function. Adv. Exp. Med. Biol. 2020, 1195, 237–247.
  16. Di Leva, G.; Garofalo, M.; Croce, C.M. MicroRNAs in cancer. Annu. Rev. Pathol. 2014, 9, 287–314.
  17. Ghosh, R.D.; Pattatheyil, A.; Roychoudhury, S. Functional Landscape of Dysregulated MicroRNAs in Oral Squamous Cell Carcinoma: Clinical Implications. Front. Oncol. 2020, 10, 619.
  18. Mehterov, N.; Sacconi, A.; Pulito, C.; Vladimirov, B.; Haralanov, G.; Pazardjikliev, D.; Nonchev, B.; Berindan-Neagoe, I.; Blandino, G.; Sarafian, V. A novel panel of clinically relevant miRNAs signature accurately differentiates oral cancer from normal mucosa. Front. Oncol. 2022, 12, 1072579.
  19. Wu, M.; Duan, Q.; Liu, X.; Zhang, P.; Fu, Y.; Zhang, Z.; Liu, L.; Cheng, J.; Jiang, H. MiR-155-5p promotes oral cancer progression by targeting chromatin remodeling gene ARID2. Biomed. Pharmacother. 2020, 122, 109696.
  20. D’Souza, W.; Kumar, A. microRNAs in oral cancer: Moving from bench to bed as next generation medicine. Oral Oncol. 2020, 111, 104916.
  21. Baba, O.; Hasegawa, S.; Nagai, H.; Uchida, F.; Yamatoji, M.; Kanno, N.I.; Yamagata, K.; Sakai, S.; Yanagawa, T.; Bukawa, H. MicroRNA-155-5p is associated with oral squamous cell carcinoma metastasis and poor prognosis. J. Oral Pathol. Med. Off. Publ. Int. Assoc. Oral Pathol. Am. Acad. Oral Pathol. 2016, 45, 248–255.
  22. Liu, Z.M.; Bao, Y.; Li, T.K.; Di, Y.B.; Song, W.J. MKI67 an potential oncogene of oral squamous cell carcinoma via the high throughput technology. Medicine 2022, 101, e32595.
  23. Erfanparast, L.; Taghizadieh, M.; Shekarchi, A.A. Non-Coding RNAs and Oral Cancer: Small Molecules With Big Functions. Front. Oncol. 2022, 12, 914593.
  24. D’Cruz, A.; Dechamma, P.N.; Saldanha, M.; Maben, S.; Shetty, P.; Chakraborty, A. Non-Invasive Saliva-based Detection of Gene Mutations in Oral Cancer Patients by Oral Rub and Rinse Technique. Asian Pac. J. Cancer Prev. APJCP 2021, 22, 3287–3291.
  25. Liu, B.; Hu, J.; Zhao, H.; Zhao, L.; Pan, S. MicroRNA-155-5p Contributes to 5-Fluorouracil Resistance Through Down-Regulating TP53INP1 in Oral Squamous Cell Carcinoma. Front. Oncol. 2021, 11, 706095.
  26. Aali, M.; Mesgarzadeh, A.H.; Najjary, S.; Abdolahi, H.M.; Kojabad, A.B.; Baradaran, B. Evaluating the role of microRNAs alterations in oral squamous cell carcinoma. Gene 2020, 757, 144936.
  27. Hu, S.; Wang, H.; Yan, D.; Lu, W.; Gao, P.; Lou, W.; Kong, X. Loss of miR-16 contributes to tumor progression by activation of tousled-like kinase 1 in oral squamous cell carcinoma. Cell Cycle 2018, 17, 2284–2295.
  28. Rishabh, K.; Khadilkar, S.; Kumar, A.; Kalra, I.; Kumar, A.P.; Kunnumakkara, A.B. MicroRNAs as Modulators of Oral Tumorigenesis-A Focused Review. Int. J. Mol. Sci. 2021, 22, 2561.
  29. Wang, X.; Li, G.H. MicroRNA-16 functions as a tumor-suppressor gene in oral squamous cell carcinoma by targeting AKT3 and BCL2L2. J. Cell. Physiol. 2018, 233, 9447–9457.
  30. Manikandan, M.; Deva Magendhra Rao, A.K.; Arunkumar, G.; Manickavasagam, M.; Rajkumar, K.S.; Rajaraman, R.; Munirajan, A.K. Oral squamous cell carcinoma: microRNA expression profiling and integrative analyses for elucidation of tumourigenesis mechanism. Mol. Cancer 2016, 15, 28.
  31. Troiano, G.; Mastrangelo, F.; Caponio, V.C.A.; Laino, L.; Cirillo, N.; Lo Muzio, L. Predictive Prognostic Value of Tissue-Based MicroRNA Expression in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-analysis. J. Dent. Res. 2018, 97, 759–766.
  32. Maclellan, S.A.; Lawson, J.; Baik, J.; Guillaud, M.; Poh, C.F.; Garnis, C. Differential expression of miRNAs in the serum of patients with high-risk oral lesions. Cancer Med. 2012, 1, 268–274.
  33. Khalil, M.I.; Madere, C.; Ghosh, I.; Adam, R.M.; De Benedetti, A. Interaction of TLK1 and AKTIP as a Potential Regulator of AKT Activation in Castration-Resistant Prostate Cancer Progression. Pathophysiol. Off. J. Int. Soc. Pathophysiol. 2021, 28, 339–354.
  34. Liu, L.; Jiang, H.; Zhao, J.; Wen, H. MiRNA-16 inhibited oral squamous carcinoma tumor growth in vitro and in vivo via suppressing Wnt/β-catenin signaling pathway. OncoTargets Ther. 2018, 11, 5111–5119.
  35. Peng, C.Y.; Liao, Y.W.; Lu, M.Y.; Yu, C.H.; Yu, C.C.; Chou, M.Y. Downregulation of miR-1 enhances tumorigenicity and invasiveness in oral squamous cell carcinomas. J. Formos. Med. Assoc. 2017, 116, 782–789.
  36. Wang, Z.; Wang, J.; Chen, Z.; Wang, K.; Shi, L. MicroRNA-1-3p inhibits the proliferation and migration of oral squamous cell carcinoma cells by targeting DKK1. Biochem. Cell Biol. 2018, 96, 355–364.
  37. Koshizuka, K.; Hanazawa, T.; Fukumoto, I.; Kikkawa, N.; Matsushita, R.; Mataki, H.; Mizuno, K.; Okamoto, Y.; Seki, N. Dual-receptor (EGFR and c-MET) inhibition by tumor-suppressive miR-1 and miR-206 in head and neck squamous cell carcinoma. J. Hum. Genet. 2017, 62, 113–121.
  38. Organ, S.L.; Tsao, M.S. An overview of the c-MET signaling pathway. Ther. Adv. Med. Oncol. 2011, 3, S7–S19.
  39. Al Rawi, N.; Elmabrouk, N.; Abu Kou, R.; Mkadmi, S.; Rizvi, Z.; Hamdoon, Z. The role of differentially expressed salivary microRNA in oral squamous cell carcinoma. A systematic review. Arch. Oral Biol. 2021, 125, 105108.
  40. Hunt, S.; Jones, A.V.; Hinsley, E.E.; Whawell, S.A.; Lambert, D.W. MicroRNA-124 suppresses oral squamous cell carcinoma motility by targeting ITGB1. FEBS Lett. 2011, 585, 187–192.
  41. Salazar-Ruales, C.; Arguello, J.V.; Lopez-Cortes, A.; Cabrera-Andrade, A.; Garcia-Cardenas, J.M.; Guevara-Ramirez, P.; Peralta, P.; Leone, P.E.; Paz, Y.M.C. Salivary MicroRNAs for Early Detection of Head and Neck Squamous Cell Carcinoma: A Case-Control Study in the High Altitude Mestizo Ecuadorian Population. BioMed Res. Int. 2018, 2018, 9792730.
  42. Li, X.; Fan, Q.; Li, J.; Song, J.; Gu, Y. MiR-124 down-regulation is critical for cancer associated fibroblasts-enhanced tumor growth of oral carcinoma. Exp. Cell Res. 2017, 351, 100–108.
  43. Qiao, C.Y.; Qiao, T.Y.; Jin, H.; Liu, L.L.; Zheng, M.D.; Wang, Z.L. LncRNA KCNQ1OT1 contributes to the cisplatin resistance of tongue cancer through the KCNQ1OT1/miR-124-3p/TRIM14 axis. Eur. Rev. Med. Pharmacol. Sci. 2020, 24, 200–212.
  44. Xu, M.; Wang, Y.; Xia, R.; Wei, Y.; Wei, X. Role of the CCL2-CCR2 signalling axis in cancer: Mechanisms and therapeutic targeting. Cell Prolif. 2021, 54, e13115.
  45. Shen, W.; Jin, Z.; Tong, X.; Wang, H.; Zhuang, L.; Lu, X.; Wu, S. TRIM14 promotes cell proliferation and inhibits apoptosis by suppressing PTEN in colorectal cancer. Cancer Manag. Res. 2019, 11, 5725–5735.
  46. Jia, L.F.; Wei, S.B.; Mitchelson, K.; Gao, Y.; Zheng, Y.F.; Meng, Z.; Gan, Y.H.; Yu, G.Y. miR-34a inhibits migration and invasion of tongue squamous cell carcinoma via targeting MMP9 and MMP14. PLoS ONE 2014, 9, e108435.
  47. Manzano-Moreno, F.J.; Costela-Ruiz, V.J.; Garcia-Recio, E.; Olmedo-Gaya, M.V.; Ruiz, C.; Reyes-Botella, C. Role of Salivary MicroRNA and Cytokines in the Diagnosis and Prognosis of Oral Squamous Cell Carcinoma. Int. J. Mol. Sci. 2021, 22, 12215.
  48. Jadhav, K.B.; Shah, V.; Chauhan, N.; Shah, N.; Parmar, G. Expression of microRNA-21 in saliva and tumor tissue of patients with oral squamous cell carcinoma: A predictor of cervical lymph node metastasis. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2022, 133, 60–69.
  49. Li, T.; Li, L.; Li, D.; Wang, S.; Sun, J. MiR-34a inhibits oral cancer progression partially by repression of interleukin-6-receptor. Int. J. Clin. Exp. Pathol. 2015, 8, 1364–1373.
  50. Li, Y.Y.; Tao, Y.W.; Gao, S.; Li, P.; Zheng, J.M.; Zhang, S.E.; Liang, J.; Zhang, Y. Cancer-associated fibroblasts contribute to oral cancer cells proliferation and metastasis via exosome-mediated paracrine miR-34a-5p. EBioMedicine 2018, 36, 209–220.
  51. Piotrowski, I.; Zhu, X.; Saccon, T.D.; Ashiqueali, S.; Schneider, A.; de Carvalho Nunes, A.D.; Noureddine, S.; Sobecka, A.; Barczak, W.; Szewczyk, M.; et al. miRNAs as Biomarkers for Diagnosing and Predicting Survival of Head and Neck Squamous Cell Carcinoma Patients. Cancers 2021, 13, 3980.
  52. Rokavec, M.; Oner, M.G.; Li, H.; Jackstadt, R.; Jiang, L.; Lodygin, D.; Kaller, M.; Horst, D.; Ziegler, P.K.; Schwitalla, S.; et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J. Clin. Investig. 2014, 124, 1853–1867.
  53. Gobin, E.; Bagwell, K.; Wagner, J.; Mysona, D.; Sandirasegarane, S.; Smith, N.; Bai, S.; Sharma, A.; Schleifer, R.; She, J.X. A pan-cancer perspective of matrix metalloproteases (MMP) gene expression profile and their diagnostic/prognostic potential. BMC Cancer 2019, 19, 581.
  54. Zhu, C.; Wei, Y.; Wei, X. AXL receptor tyrosine kinase as a promising anti-cancer approach: Functions, molecular mechanisms and clinical applications. Mol. Cancer 2019, 18, 153.
  55. Ge, X.; Gao, J.; Sun, Q.W.; Wang, C.X.; Deng, W.; Mao, G.Y.; Li, H.Q.; Guo, S.S.; Cheng, J.; Wu, Y.N.; et al. MiR-34a inhibits the proliferation, migration, and invasion of oral squamous cell carcinoma by directly targeting SATB2. J. Cell. Physiol. 2020, 235, 4856–4864.
  56. Roy, S.K.; Shrivastava, A.; Srivastav, S.; Shankar, S.; Srivastava, R.K. SATB2 is a novel biomarker and therapeutic target for cancer. J. Cell. Mol. Med. 2020, 24, 11064–11069.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback