The oncogenic role of miR-155 on oral cancer progression and treatment strategies

Abstract

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy within head and neck cancers, often associated with risk factors such as tobacco use, alcohol consumption, and HPV infection. MicroRNAs (miRNAs), small non-coding RNAs that inhibit target genes, are a promising new focus as biomarkers or therapeutic targets for cancer treatment. miR-155 has emerged as a significant regulator in various cancers, including OSCC, where its altered expression is linked to tumor initiation, progression, and resistance to treatment. miR-155 is a well-studied miRNA that has an oncogenic role in several solid tumors, including oral cancer. Studies suggest that miR-155 modulates key cellular processes such as proliferation, apoptosis, and immune response, making it a promising biomarker and potential therapeutic target. Investigating the mechanisms through which miR-155 drives OSCC progression could pave the way for enhanced diagnostic and therapeutic approaches, addressing essential needs in managing this aggressive cancer type. The present paper highlights the oncogenic role of miR-155 in oral cancers, summarizing recent advancements in therapeutically targeting this transcript, including preclinical testing of miR-155 inhibitors. This approach offers a promising new avenue for treating drug-resistant oral cancer.

Introduction

Oral cancer encompasses a group of diseases affecting various anatomical regions within the oral cavity, including the lips, hard palate, upper and lower alveolar ridges, anterior two-thirds of the tongue, sublingual region, buccal mucosa, retromolar trigone and floor of the mouth [1]. Based on histological classification, squamous cell carcinoma accounts for over 90% of oral cancer cases. Consequently, the term ‘oral cancer’ is often used interchangeably with oral squamous cell carcinoma (OSCC) [1].

The development of OSCC is a multistep process, frequently involving intermediate oral potentially malignant disorders (OPMDs), such as leukoplakia and erythroplakia [2]. OSCC has the highest mortality rate among head and neck cancers, with a general life expectancy of less than 5 years [2–4].

The lack of specific biomarkers, poor patient survival, and high tumor recurrence rates present significant clinical challenges in managing oral cancer [5]. Current research focuses on identifying biomarkers for early diagnosis, treatment response and survival predictors, and novel therapeutic targets, emphasizing the altered expression of coding and non-coding genes.

MicroRNAs (miRNAs), small non-coding RNAs, are critical in regulating gene expression by targeting specific mRNAs for degradation or translational repression, influencing various cellular pathways [6, 7]. Each miRNA is synthesized as a duplex comprising two strands (5p and 3p). Aberrations in miRNA expression - upregulation or downregulation - are frequently observed in pathological processes, where they can target a wide range of mRNA sequences and exert diverse roles [3, 5].

Studies have extensively investigated the altered expression of miRNAs in OSCC, spanning diagnosis to treatment response determination [8]. Some miRNAs correlate with survival rates and other clinical features [9]. Mechanistic studies reveal that numerous miRNAs show altered expression levels in OSCC, correlating with disease stages, progression, or risk of metastasis. These findings underscore the potential for miRNAs to improve clinical outcomes, enabling better diagnosis, prognosis (e.g., identifying patients with poor outcomes), and stratification based on responsiveness to chemotherapy or radiotherapy.

In cancer, miRNAs can act as oncogenes (oncomiRs) or tumor suppressors, depending on the cellular context and their mRNA targets [8, 10]. Oncogenic miRNAs promote tumorigenesis by downregulating tumor suppressor genes, while tumor-suppressive miRNAs inhibit cancer progression by targeting oncogenes. The main oncogenic microRNAs implicated in OSCC include miR-21 [11, 12], miR-31 [13], miR-34 [14], miR-155, and miR-146a [15–17], each contributing to tumor initiation, progression, and therapy resistance through the downregulation of tumor suppressor genes and the modulation of key oncogenic signaling pathways such as PI3K/AKT, NF-κB, and STAT3 [11–14, 17].

We selected miR-155 for in-depth analysis due to its well-documented role as a multifunctional oncogenic microRNA in various cancers, including OSCC, where it has been shown to promote tumor progression, inflammation-mediated carcinogenesis, and resistance to therapy by targeting key tumor suppressor genes and modulating immune responses. Its elevated expression in both tissue and liquid biopsies further highlights its potential as a diagnostic biomarker and therapeutic target in OSCC.

Alteration of miR-155 expression levels in OSCC

The dysregulation of miR-155 expression is a critical focus in OSCC research due to its frequent alteration in many malignancies. Beyond OSCC, miR-155 is dysregulated in various cancers, including lung, breast, pancreatic, prostate, gastric, colorectal, endometrial, melanoma, glioblastoma, osteosarcoma, and thyroid cancer [18–21]. This extensive dysregulation underscores the role of miR-155 as a pivotal oncogenic transcript and a potential universal biomarker in cancer biology [19]. Numerous studies on oral carcinogenesis have identified miR-155 as significantly overexpressed in oral cancer compared to normal oral tissue [22–25].

This overexpression correlates with key clinical parameters such as tumor size, TNM stage [26]histological grade [25] and lymph node metastasis [22]. Furthermore, elevated levels of miR-155 in OSCC are associated with poor prognosis [22, 26, 27]. Specifically, miR-155-5p overexpression has been identified as a marker of epithelial–mesenchymal transition (EMT)-associated OSCC progression and is highlighted in the literature as a predictive biomarker for relapse, particularly in early-stage patients [26]. Previously, we included miR-155-5p into a novel miRNA panel alongside miR-21-5p, miR-93-5p, miR-133b, miR-146b-5p, and miR-182-5p. This panel was proposed as an OSCC-specific molecular signature with both diagnostic and prognostic significance, demonstrating strong correlations with disease-free survival. The panel was developed based on data from two independent patient cohorts and further validated using The Cancer Genome Atlas (TCGA) dataset [28]. Other studies have also identified. miR-155, miR-191, and miR-494 as diagnostic biomarkers for OSCC [29]. Additionally, miR-155 and miR-200c have been linked to clinical-pathological features of salivary gland tumors [30]. Low-grade mucoepidermoid carcinoma, for example, exhibits elevated miR-155 expression [30]. In head and neck squamous cell carcinoma (HNSCC) patients, the upregulation of miR-155, along with miR-21 and the downregulation of miR-422, has been associated with smoking exposure, making these transcripts valuable markers for cancer progression in smokers [31]. Similarly, miR-155 overexpression has been strongly correlated with smoking history in OSCC, with significantly higher expression levels in smokers compared to non-smokers [32]. A meta-analysis summarizing eight studies indicates a direct correlation between miR-155 expression and survival outcomes in HNSCC patients, reporting hazard ratios (HR) of 1.40 for overall survival (OS), 1.36 for disease-free survival (DFS), and 1.09 for progression-free survival (PFS) [24]. Manikandan et al. highlighted a correlation between miR-155 overexpression and tobacco, or betel quid use in the Indian population [32]. Other studies also linked miR-155 overexpression to tobacco chewing habits [5]. Furthermore, miR-155 expression has been associated with HPV-positivity, high CD8⁺ tumor-infiltrating lymphocyte (TIL) counts, and improved survival outcomes [33].

Moreover, research conducted by Zhou et al. highlights that the simultaneous overexpression of miR-155-5p and inhibition of miR-223-3p synergistically drives partial epithelial–mesenchymal transition (pEMT). This process enhances tumor cell invasiveness and metastasis while maintaining certain epithelial features. Modifying miR-155-5p and miR-223-3p contributes to greater OSCC aggressiveness, including increased cell migration, invasion, and metastatic potential [34]. Both miR-155-5p and miR-1246 were identified as significantly overexpressed in OSCC patients compared to healthy controls, highlighting their utility as non-invasive diagnostic markers; moreover, their elevated levels were correlated with poorer clinical outcomes, including advanced tumor stage and reduced overall survival, underscoring their prognostic significance.

The role of salivary miRNAs in OSCC occurrence and progression has scarcely been studied. In a study including 61 patients with OSCC, Burtyn et al. found that in the saliva of healthy controls, the level of miR-155 was 2.84 times lower (p < 0.05) than in the OSCC cases. Further analysis of the association between the clinicopathological features and miRNAs revealed that the up-regulation of miR-21 and miR-155 expression and down-regulation of miR-375 levels are associated with a more advanced stage of OSCC. Moreover, the miR-21 and miR−155 levels positively correlated with the T index by TNM (r = 0.68 and r = 0.75, respectively) (p < 0.05), and higher levels were observed in the saliva of patients with lymph node metastases (r = 0.78 and r = 0.71, respectively) (p < 0.05) [35]. However, those observations were not consistent with those of other studies [36]. This body of evidence emphasizes the critical role of miR-155 in OSCC progression and its potential as a diagnostic, prognostic, and therapeutic biomarker in various clinical and population-specific contexts, as summarized in Fig. 1; Table 1.

Fig. 1.

Role of miR-155 in Oral Squamous Cell Carcinoma (OSCC). The multifaceted role of miR-155 in OSCC highlights its association with risk factors such as smoking, betel quid or tobacco chewing, alcohol consumption, HPV infection (especially HPV16), environmental carcinogens, and epigenetic alterations. Overexpression of miR-155 is linked to OSCC development and progression by altering gene regulation targeting cancer pathways, promoting cancer cell migration and invasion, and modulating the tumor microenvironment components, thereby enhancing tumor progression. In vitro studies suggest that miR-155 upregulation correlates with poor prognosis. Targeting miR-155 presents a promising therapeutic strategy for OSCC management

Table 1.

The increased expression levels of miR-155 in pathological conditions

Pathology	Cohort	Observation	References
OSCC	The initial identification was conducted using 34 paired OSCC samples from a Bulgarian patient cohort, followed by validation in 74 paired OSCC samples from an Italian patient cohort and 354 OSCC samples from the TCGA dataset.	miRNA signature (miR-21-5p, miR-93-5p, miR-133b, miR-146b-5p, miR-155-5p and miR-182-5p) with diagnostic and prognostic value that differentiated OSCC from normal mucosa	[28]
OSCC	50 matched paired OSCC tumor and normal adjacent tissue	Prognostic markers; predict the response to Avastin	[28]
OSCC	68 patients with OSCC	Tumor relapse	[26]
OSCC	42 OSCC tumors and eight adjacent normal specimens	Correlated with the habit of chewing tobacco/betel quid	[32]
OSCC	73 subjects with OSCC and 5 controls	Associated with metastasis and poor prognosis	[22]
OSCC	12 primary OSCC tissues and matching adjacent non-tumor tissues	–	[37]
OSCC	22 matched OSCC samples and normal oral tissues	Therapeutic target	[38]
OSCC	Serum from healthy volunteers (n = 7), healthy smoker/tobacco (n = 6) primary tumor (n = 7), and recurrence tumor patients that had received cisplatin treatment (n = 6).	Overexpression in smokers vs. non-smokers; overexpression in recurrent cases vs. OSCC, and healthy controls	[39]
OSCC	46 cases of OSCC and 25 normal oral mucosa samples	Therapeutic target	[40]
OSCC	40 matched cases (TNM stage I and II samples vs. autologous normal mucosa-controlled)	Involved in carcinogenesis	[25]
OSCC	46 cases of OSCC	Prognostic biomarker; correlated with histological grade	[25]
PA, MEC, and ACC	–	EMT, correlated with clinical parameters	[30]
Tongue	18 matched samples	Progression of tumorigenesis	[18]
Tonsillar and base of tongue SCC	–	Positive predictor of survival, with the effect mainly due to its association with high CD8+ TIL numbers; miR-155 predicts outcome in HPV+ patients	[33]
OSCC	50 OSCC cases, with adjacent normal mucosa as controls	miR-155 high expression has prognostic significance related to advanced tumor stage and reduced overall survival.	[23]
OSCC	Saliva samples obtained from 61 OSCC patients	miR-155 high expression in saliva; correlates with the T index by TNM, higher in patients with lymph node metastasis	[11]

ACC adenoid cystic carcinoma, MEC mucoepidermoid carcinoma, PA pleomorphic adenoma

Expression of miR-155 in liquid biopsy samples from OSCC patients

Recent advances in non-invasive diagnostic strategies have emphasized the utility of circulating miRNAs as promising biomarkers, particularly in liquid biopsy samples such as plasma and saliva [41–44]. This makes miR-155 a compelling candidate for early detection and real-time monitoring of disease progression or therapeutic response, as was observed from a recent study head and neck squamous cell carcinomas along with miR-21 and miR-375 [45], orhte study presents same transcripts signature OSCC salivary progrnostic signature corelated with TNM [11]. Elevated levels of miR-155, miR-191, and miR-494 were detected in the peripheral blood of OSCC patients compared to healthy individuals. Interestingly, treatment with Avastin (400 µM) mAbs was shown to reduce the expression levels of all three biomarkers [28].

Extracellular vesicles, including exosomes, play a crucial role in regulating and modulating tumor progression by transferring proteins, lipids, nucleic acids, and particular miRNAs [46, 47]. Several studies have highlighted the impact of exosome-derived miRNAs on OSCC prognosis [47–49]. miR-155 expression in exosomes isolated from the serum of individuals with a history of tobacco use was found to be significantly higher than that of healthy control volunteers. Dysregulated exosomal miR-155 expression was also observed in oral cancer patients, with overexpression particularly evident in OSCC patients who experienced disease recurrence following cisplatin chemotherapy. This pattern was significant not only when compared to healthy controls but also when compared to other OSCC patients without recurrence [39].

In preclinical models, exosomal miR-155 inhibitors successfully suppressed stem-cell-like traits and drug efflux transporter protein expression in cisplatin-resistant OSCC models. This suggests that exosomes loaded with miR-155 inhibitors could be a potential strategy for overcoming chemoresistance in oral cancer [1].

miR-155 in preclinical studies

miR-155, processed from the B cell integration cluster (BIC), also known as MIR155HG (miR-155 host gene), plays a significant role in cancer biology [50]. Overexpression of miR-155 is commonly associated with increased cell growth, invasion, migration, stemness, and angiogenesis across various solid tumors [27, 51].

As a critical gene regulatory element, miR-155 is implicated in the carcinogenesis of various epithelial tumors. It influences key biological processes such as tumor cell proliferation, cell death mechanisms, invasion, and other tumor-related behaviors [37].

One of the significant cancer pathways is increased cell proliferation, which leads to enhanced tumor growth, as presented in Fig. 2. Moreover, the ability of tumor cells to migrate and invade is essential for spreading to the lymph nodes and blood vessels [38]. miR-155 promotes migration and invasion of various cancers, including OSCC. Studies show that miR-155 enhances the migration and invasion capabilities of OSCC cells [38]. Notably, treatment with melatonin was found to reduce miR-155 expression levels in extracellular vesicles derived from OSCC, suggesting a potential therapeutic approach for targeting this miRNA [46]. The most relevant preclinical data related to the implication of miR-155 in OSCC are presented in Table 2.

Fig. 2.

OSCC pathways associated with miR-155. This figure illustrates the key oncogenic processes driven by miR-155 overexpression in OSCC. miR-155 promotes sustained proliferation by modulating the PI3K/AKT pathway through PTEN suppression and enhancing cell cycle progression. It contributes to immune evasion by downregulating SOCS1, leading to STAT3 activation. miR-155 facilitates invasion and metastasis by downregulating ARID2 and E-cadherin while upregulating Vimentin, promoting epithelial-to-mesenchymal transition (EMT). Additionally, miR-155 aids in evading apoptosis by targeting FOXO3A and TP53INP1 and supports angiogenesis induction. Tumor suppressor genes are marked in green, while upregulated and downregulated factors are indicated with red and orange, respectively. Distinct arrows represent suppression, stimulation, and sustained proliferation

Table 2.

miR-155 upregulation targets key biological processes

Pathology	Treatment	Study model/cell lines	Target genes	Relevance for target pathology and its biological functions	References
OSCC	5-FU resistant/miR-155-5p inhibitors	HSC3/5-FU, HSC3, HSC4	TP53INP1	Resistance to 5-FU/reconversion of resistance	[27]
OSCC	Melatonin	SCC9, SCC25 and CAL27	–	miR-155 is a key element in melatonin-associated anti-tumor effects.	[46]
OSCC	miR-155 mimic	SCC131 (cisSen) its cisplatin-resistant derivative (cisRes)	FOXO3A.PI3K/AKT	Exosome mediated miR-155 delivery confers cisplatin chemoresistance in oral cancer cells via epithelial–mesenchymal transition	[39]
OSCC	miR-155 mimic and inhibitor	CAL27 and NOK-SI	BCL6, CCND2	Regulated cell proliferation, invasion and metastasis	[37]
OSCC	cDNA3.1(+)-bic construct; use of antagomiR-155	KB, SCC084, SCC131 and xenograft model	CDC73	Knockdown of CDC73 expression due to overexpression of miR-155; restoration of CD 73 levels	[38]
OSCC	miR-155 mimic and inhibitor	SCC131 (cisSen), SCC131 (cisRes)	FOXO3a	EMT, cell motility	[39]
OSCC	MiR-155 inhibitor-loaded exosomes	3D Tumor Spheroid and Xenograft Model	FOXO3a	Resistance to cisplatin, EMT and stem cells features	[52]
OSCC	miR-155 inhibitor	Tca8113	p27Kip1	Cell proliferation, cycle, and apoptosis	[40]
OSCC	miR-155-5p mimic or inhibitor	HSC-3	STAT3/SOCS1	Cell proliferation and migration, EMT	[22]
OSCC	miR-155 precursor	HSC-3, SCC-4, HIOEC-B	–	Cell proliferation	[25]
Tongue OSCC	pLCE–miR-155 sponge	SAS cells	Pdcd4, AP-1	Increases apoptosis, arrests the cell cycle, regresses tumor size in xenograft nude mice, and reduces cell viability and colony formation in soft-agar and clonogenic assays	[18]
OSCC	miR-155	SCC4, SCC9, SCC15, SCC25, and CAL27.	↑MBTD1 and FSCN1; ↓CLCN3, FLI1, MRTFB, DAB, SRGAP1, BHD17C	Design targets or treatments to reduce chemotherapy resistance and improve patient treatment outcomes.	[53]

Drug resistance in OSCC

Drug resistance in OSCC represents a significant barrier to effective treatment, significantly reducing the success of standard chemotherapy and radiotherapy. This resistance often arises from multiple adaptive mechanisms within tumor cells, including enhanced DNA repair capacity, altered drug metabolism, increased drug efflux, and evasion of apoptosis [54–56]. Transcriptomic alterations in coding and non-coding genes are closely linked to cell proliferation, survival, and immune evasion processes [55–57]. Addressing and targeting these resistance pathways is crucial for improving therapeutic outcomes in OSCC.

Recent findings suggest that several miRNAs, including miR-155, play pivotal roles in mediating the response of oral cancer to chemotherapy [58]. Overexpression of miR-155 has been identified as a driver of multidrug resistance in multiple cancers, including OSCC. As a result, miR-155-mediated signaling pathways have emerged as promising targets for molecular cancer therapy [50].

miR-155 is implicated in various pathways, particularly those influencing the chemotherapeutic responsiveness to agents like Paclitaxel [58] and 5-fluorouracil (5-FU) [27]. Studies show that resistance to these drugs can be counteracted with miR-155 inhibitors, which function via a novel TP53INP1/miR-155 feedback loop [27]. Resistance of OSCC cell lines to 5-FU was associated with the overexpression of miR-155, which inhibits TP53INP1- a critical tumor suppressor gene regulated by TP53 ²⁷. TP53INP1 plays a vital role in cell death, cell-cycle arrest, and cellular migration [59]. Moreover, miR-155 was overexpressed in cisplatin-resistant OSCC cells compared to cisplatin-sensitive ones. This pattern was similarly observed in patients with disease recurrence after cisplatin therapy [39]. The role of miR-155 in inducing chemoresistance highlights the potential of miR-155-targeted therapies to overcome drug resistance in OSCC.

miR-155 regulates EMT, invasion, migration and metastasis in OSCC

Epithelial-to-mesenchymal transition (EMT) is a crucial biological process that drives the loss of cell adhesion, promoting invasion and metastasis [30]. miR-155 has been shown to regulate EMT and its related mechanisms, thereby influencing cancer progression and chemoresistance. miR-155 inhibitor-loaded exosomes were able to reverse chemoresistance in 3D tumor spheroid and xenograft models of oral cancer. In preclinical studies, miR-155 inhibitor-loaded exosomes were able to reverse chemoresistance in 3D tumor spheroid and xenograft models of oral cancer. This effect was achieved through the overexpression of FOXO3a, which is linked to cell proliferation and the suppression of EMT mechanisms. The inhibition of EMT improved cisplatin sensitivity, suggesting a valuable therapeutic strategy for recurrent OSCC cases [52]. Notably, exosome-mediated miR-155 delivery was shown to confer cisplatin chemoresistance in oral cancer cells through EMT activation [39, 46].

Transfection with miR-155-5p inhibitor in HSC-3 cells led to the overexpression of SOCS1 and downregulation of STAT3. These changes impacted key EMT markers, increasing E-cadherin levels and reducing N-cadherin and vimentin mRNAs [22].

Cancer metastasis is closely tied to the EMT process, and miR-155-5p promotes EMT through an ARID2/Snail-dependent pathway. Downregulation of ARID2, a key component of the SWI/SNF transcriptional complex, altered the activity of the transcription factor Snail. This, in turn, affected the expression of EMT-related proteins such as E-cadherin and vimentin, ultimately enhancing cell invasion and metastasis.

Conclusions

miR-155 is increasingly recognized not only as a biomarker for diagnosing and predicting the prognosis of oral cancer but also as a promising therapeutic target due to its critical role in regulating tumor development and progression. In OSCC, miR-155 overexpression has been linked to aggressive tumor behavior, including advanced disease stages, metastasis, and post-treatment relapse. These correlations highlight its dual potential as both a prognostic marker and a driver of cancer progression.

Functional studies using OSCC cell lines and animal models have revealed several key pathways influenced by miR-155 overexpression. Specifically, miR-155 dysregulation affects cell proliferation, survival, inflammation, and immune responses, all contributing to OSCC aggressiveness. For example, miR-155 has been shown to inhibit tumor suppressor genes and modulate oncogenic signaling pathways, fostering an environment that supports rapid tumor growth, invasion, and resistance to therapy. While some pathways have been elucidated, much remains to be understood about the complex network of interactions and regulatory loops involving miR-155.

Further research is needed to map these pathways comprehensively, as doing so could uncover additional therapeutic targets and clarify the mechanisms driving the role of miR-155 in OSCC. A deeper understanding of these networks will be crucial for developing targeted therapies that modulate miR-155 activity, potentially paving the way for treatments that mitigate tumor progression, prevent metastasis, and overcome therapeutic resistance. By delving into the intricate regulatory landscape influenced by miR-155, researchers hope to advance precision medicine approaches, offering personalized and more effective treatment strategies for patients with oral cancer.

Author contributions

A.I.A., C.B. and N.M. contributed equally to the conception and design of the review. A.I.A., N.M., A.N., B.V., B.N., and C.K. conducted the literature search, data collection, and analysis. A.I.A. and N.M. drafted the manuscript. R.B., C.B., and I.B.-N. provided critical revisions, conceptual insights, and supervision. All authors contributed to the manuscript’s review and editing, approved the final version, and agreed to be accountable for the content and integrity of the work.

Funding

NM and CKK thank to European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project № BG-RRP-2.004-0007-C01.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.