Is OLP potentially malignant? A clue from ZNF582 methylation.

OBJECTIVE: Whether oral lichen planus (OLP) was potentially malignant remains controversial. Here, we examined associations of ZNF582 methylation (ZNF582m ) with OLP lesions, dysplastic features and squamous cell carcinoma (OSCC). MATERIALS AND METHODS: This is a case-control study. ZNF582m was evaluated in both lesion and adjacent normal sites of 42 dysplasia, 90 OSCC and 43 OLP patients, whereas ZNF582m was evaluated only in one mucosal site of 45 normal controls. High-risk habits affecting ZNF582m such as betel nut chewing and cigarette smoking were also compared in those groups. RESULTS: OLP lesions showed significantly lower ZNF582m than those of dysplasia and OSCC. At adjacent normal mucosa, ZNF582m increased from patients of OLP, dysplasia, to OSCC. In addition, ZNF582m at adjacent normal sites in OLP patients was comparable to normal mucosa in control group. Dysplasia/OSCC patients with high-risk habits exhibited significantly higher ZNF582m than those without high-risk habits. However, ZNF582m in OLP patients was not affected by those high-risk habits. CONCLUSIONS: OLP is unlikely to be potentially malignant based on ZNF582m levels. ZNF582m may also be a potential biomarker for distinguishing OLP from true dysplastic features and OSCC, and for monitoring the malignant transformation of OLP, potentially malignant disorders with dysplastic features and OSCC.

Improving the Diagnostic Performance by Adding Methylation Marker to Conventional Visual Examination in Identifying Oral Cancer.

BACKGROUND: Visual oral examination (VOE) is a conventional oral cancer screening method. This study aimed to evaluate the value of methylation marker to assist VOE in identifying oral epithelial dysplasia and oral squamous cell carcinoma (OED/OSCC) from non-cancerous lesions in a real-world situation. METHODS: 201 patients with high-risk personal habits who self-perceived oral anomaly were VOE examined, ZNF582 methylation (ZNF582m) tested, and histologically diagnosed. RESULTS: Among them, 132 patients (65.7%) were histologically diagnosed OED/OSCC. Using VOE, 56.1% OED/OSCC patients had possible oral cancer, whereas 37.7% non-OED/OSCC patients had leukoplakia. ZNF582m-positive was detected in 90.2% OED/OSCC patients and 44.9% non-OED/OSCC patients. Various logistic regression models were postulated to evaluate the diagnostic performance of conventional VOE and new strategies using ZNF582m. ROC analysis and its corresponding C-index demonstrated that either triage or co-testing models of VOE and ZNF582m could improve diagnostic performance and discriminative abilities compared with the VOE only approach. CONCLUSIONS: In conclusion, methylation marker test shows equivalent performance to an experienced judgment by oral maxillofacial surgeons and plays a significantly supplementary role in increasing the efficacy in identifying oral malignant lesions. ZNF582m may be an especially important tool for family physicians or general dentists to properly diagnose suspicious oral lesions.

Identification of plasma hsa_circ_0000190 and 0001649 as biomarkers for predicting the recurrence and treatment response of patients with oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a type of malignancy characterized by high relapse and recurrence rates in the late stage despite optimal surgical intervention and postoperative chemoradiotherapy. Because the management of relapse following definitive treatment is challenging, accurate risk stratification is of clinical significance to improve treatment outcomes. Circular RNAs (circRNAs) are noncoding RNAs featured with cell-type specificity and high stability, owing to their circular structure, making these molecules excellent biomarkers for a variety of diseases. METHODS: The levels of hsa_circ_0000190 and 0001649 in plasma samples from 30 healthy controls and 66 OSCC patients were determined by droplet digital polymerase chain reaction. The same primer sets were used with PCR to examine the expression of these two circRNAs in cancerous and adjacent normal tissues. A receiver operating characteristics curve was generated to evaluate the diagnostic value. The Kaplan-Meier method with a log-rank test was used for survival analysis. RESULTS: We identified two circRNAs as potential biomarkers for OSCC, showing that the plasma level of hsa_circ_0000190 was significantly decreased in the late stage and marginally correlated with the development of second primary OSCC. We also found that the decreased plasma hsa_circ_0001649 was correlated with the recurrence and poor prognosis of patients. Additionally, we found that high plasma hsa_circ_0000190, but not hsa_circ_0001649, possibly predicted a better response of patients to induction chemotherapy. CONCLUSION: Our study demonstrated the potential of biomarkers in plasma to inform not just the tumor but the entire oral cavity, thereby offering a prediction for early recurrence and second primary OSCC. The plasma circRNAs remain valuable for OSCC, albeit the easy accessibility to the oral cavity.

Recent progress of biomarkers in oral cancers.

Oral cancers are the seventh most common cancer globally. While progresses in oral cancer treatment have been made, not all patients respond to these therapies in the same way. To overcome this difficulty, numerous studies have been devoted to identifying biomarkers, which enable early identification of patients who may benefit from a particular treatment modality or at risk for poor prognosis. Biomarkers are protein molecules, gene expression, DNA variants, or metabolites that are derived from tumors, adjacent normal tissue or bodily fluids, which can be acquired before treatment and during follow-up, thus extending their use to the evaluation of cancer progression and prediction of treatment outcome. In this review, we employed a basic significance level (<0.05) as the minimal requirement for candidate biomarkers. Effect sizes of the biomarkers in terms of odds ratio, hazard ratio, and area under the receiver operating characteristic curves were subsequently used to evaluate the potential of their clinical use. We identified the CCND1 from the tumor, human papillomavirus, HSP70, and IL-17 from the peripheral blood, and high density of CD45RO+ tumor-infiltrating lymphocytes as the clinically relevant biomarkers for oral cancers.

Effects of a simulation-based blended training model on nurses' treatment decision-related knowledge about oral cancer in Taiwan: a pilot survey.

The present study aimed to evaluate the effects of virtual reality (VR) simulations combined with bedside assignments on nurses' self-efficacy in providing pre-treatment educational services. Between March 2019 and November 2020, we conducted a study of VR educational materials that were developed to cover information about the treatment of oral cancers. The effects of the VR simulation, the thinking-path tracking map method, and bedside assignments on the nurses' treatment decision-related knowledge were evaluated in a ward for oral cancer patients at Taipei Veterans General Hospital, Taipei, Taiwan. The blended training model significantly increased nurses' familiarity (P<0.01) and confidence (P<0.03) regarding their knowledge of treatments and treatment decision-related knowledge. This model also significantly increased their confidence in their skills in bedside pre-treatment education for admitted oral cancer patients (P<0.002). Oral cancer-specific VR materials enhanced the effectiveness of skills training among nurses in the oral cancer ward.

Activation of the miR-371/372/373 miRNA Cluster Enhances Oncogenicity and Drug Resistance in Oral Carcinoma Cells.

Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated deaths worldwide. Family members in miR-371/372/373 miRNA cluster, which is localized at human chromosome 19q13.4, are co-expressed in both human stem cells and malignancies. The individual miRNA in this cluster are also involved in modulating the pathogenesis of malignancies as either oncogenes or suppressors. The 19q13 region is frequently gained in head and neck cancers. High expression of miR-372 and miR-373 are survival predictors for OSCC. However, the role of the miR-371/372/373 cluster in oral carcinogenesis remains to be fully investigated. We use the clustered, regularly interspaced, short palindromic repeats (CRISPR)-Cas9 system to establish OSCC cell subclones that had the miR-371/372/373 cluster deleted. In addition, further subclones were established that had the promoter of this cluster deleted. Concordant silencing in SAS cells of miR-371/372/373 decreased oncogenic potential, increased cisplatin sensitivity, activated p53, and upregulated the expression of Bad and DKK1. We also employed the CRISPR/dCas9 synergistic activation mediator system, which allowed robust transcriptional activation of the whole miR-371/372/373 cistron. Upregulation of endogenous miR-371/372/372 expression increased both oncogenicity and drug resistance. These were accompanied by a slight activation of AKT, ß-catenin, and Src. This study identifies the oncogenic role of the miR-371/372/373 cluster in OSCC. Using CRISPR based strategy can be a powerful paradigm that will provide mechanistic insights into miRNA cluster functionality, which will also likely help the development of targeting options for malignancies.

Evaluation of factors associated with the risk stratification of survivorship for stage IV squamous cell carcinoma of the oral cavity: A 10-year retrospective study.

BACKGROUND: Oral squamous cell carcinoma (OSCC) leads to thousands of deaths every year in Taiwan. Nearly 40% of OSCC patients are diagnosed with stage IV disease, which has a poor prognosis. Multimodality treatments including surgery and adjuvant therapy have been utilized, but their treatment outcomes are generally poor. In this study, we sought to identify possible clinical impact factors that may contribute to the survival of stage IV OSCC. METHODS: Data for patients with malignant neoplasms of the oral cavity registered in the Cancer Registry Database of Taipei Veterans General Hospital between 2002 and 2011 were retrieved. The study patients consisted of OSCC patients with clinical stage IV disease who had undergone a surgery and adjuvant therapy. The primary endpoints were the 5-year disease-free survival (DFS) and overall survival (OS) rates. The clinicopathological characteristics of the patients were also stratified and compared. RESULTS: A total of 191 OSCC patients were included for retrospective analysis. The different subgroups of stage IV disease presented different treatment outcomes. The 5-year OS versus DFS rates of each subgroup were as follows: T4N0: 70.9% versus 52.6%; T1-3N23: 66.1% versus 49.8%; T4N1: 49.6% versus 31.6%; and T4N23: 40.9% versus 31.0% (p < 0.01). Patients with diabetes, moderate or poor cell differentiation, perineural invasion, and extracapsular spread presented lower 5-year OS rates (hazard ratio [HR] = 1.87, 1.65, 2.42, and 2.14, respectively), and patients with perineural invasion, positive cut margin, and extracapsular spread presented lower 5-year DFS rates (HR = 1.57, 1.62, and 1.71, respectively). CONCLUSION: In this study, we elucidated the different survival rates of different subgroups of stage IV OSCC following the same treatment scheme. The results of the study provide clinical physicians with references by which to evaluate prognosis and determine post-operative disease monitoring timetables based upon different characteristics.

The miR-372-ZBTB7A Oncogenic Axis Suppresses TRAIL-R2 Associated Drug Sensitivity in Oral Carcinoma.

miR-372 has been shown a potent oncogenic miRNA in the pathogenesis of oral squamous cell carcinoma (OSCC). The zinc finger and BTB domain containing 7A protein (ZBTB7A) is a transcriptional regulator that is involved in a great diversity of physiological and oncogenic regulation. However, the modulation of ZBTB7A in OSCC remains unclear. Tissue analysis identifies a reverse correlation in expression between miR-372 and ZBTB7A in OSCC tumors. When OSCC cells have stable knockdown of ZBTB7A, their oncogenic potential and drug resistance is increased. By way of contrast, such an increase is attenuated by expression of ZBTB7A. Screening and validation confirms that ZBTB7A is able to modulate expression of the death receptors TRAIL-R1, TRAIL-R2, Fas and p53 phosphorylated at serine-15. In addition, ZBTB7A transactivates TRAIL-R2, which sensitizes cells to cisplatin-induced apoptosis. The ZBTB7A-TRAIL-R2 cascade is involved in both the extrinsic and intrinsic cisplatin-induced pathways of apoptosis. Database analysis indicates that the expression level of and the copy status of ZBTB7A and TRAIL-R2 are important survival predictors for head and neck cancers. Collectively, this study indicates the importance of the miR-372-ZBTB7A-TRAIL-R2 axis in mediating OSCC pathogenesis and in controlling OSCC drug resistance. Therefore, silencing miR-372 and/or upregulating ZBTB7A would seem to be promising strategies for enhancing the sensitivity of OSCC to cisplatin therapy.

Cancer stem cell theory: Are we moving past the mist?

Cancer stem cells (CSC) are a subpopulation of tumor cells that have superior capacities of self-renewal, metastatic dissemination, and chemoresistance. These characteristics resemble, to some extent, the outcome of certain biological processes, including epithelial-mesenchymal transition (EMT), autophagy, and cellular stress response. Indeed, it has been shown that the stimuli that induce these processes and CSC are overlapping, and CSC and tumor cells that underwent EMT or autophagy are much alike. However, as the cross talk between CSC, EMT, autophagy, and cellular stress is further explored, these processes are also found to have an opposing role in CSC, depending on the condition and status of cells. This contextual effect is likely due to overwhelming reliance on CSC markers for their identification, and/or discrepancies in recognition of CSC as a particular cell population or cellular state. In this review, we summarize how EMT, autophagy, and cellular stress response are tied or unwound with CSC. We also discuss the current view of CSC theory evolved from the emphasis of heterogenicity and plasticity of CSC.

ASB6 Promotes the Stemness Properties and Sustains Metastatic Potential of Oral Squamous Cell Carcinoma Cells by Attenuating ER Stress.

Up-regulation of ASB6 has been previously associated with late-stage and poor prognosis of oral squamous cell carcinoma (OSCC) patients. To explore the cellular and molecular basis of how ASB6 enhances the malignancy of OSCC, we employed the clonogenicity and migration assays, murine pulmonary metastasis model, Western blot, and immunofluorescence microscopy to characterize the phenotypes of OSCC cells with lentiviral-based stable overexpression or knockdown of ASB6. We found that ASB6 overexpression increases, whereas ASB6 knockdown decreases, the potential of tumor-sphere formation, colony formation, and expression of Oct-4 and Nanog. While knockdown of ASB6 decreases cell migration in vitro and lung metastasis in mice, the migratory potential was however not promoted by ASB6 overexpression. ASB6 knockdown down-regulates the level of vimentin, and the loss of filopodia formation became more prominent following CRISPR/Cas9-directed knockout of ASB6. Moreover, ASB6 was up-regulated when cells were grown in selective condition featured with a collateral effect of enhancing intracellular stress, and the level of endoplasmic reticulum (ER) stress was further increased by knockdown of ASB6. Thus, ASB6 may attenuate ER stress that would otherwise accumulate and subsequently impede the potential of cells to acquire or sustain the stemness properties and metastatic capacity, thereby enhancing the malignancy of OSCC by increasing the population of cancer stem or stem-like cells.

Methylation and PTEN activation in dental pulp mesenchymal stem cells promotes osteogenesis and reduces oncogenesis.

Lineage commitment and tumorigenesis, traits distinguishing stem cells, have not been well characterized and compared in mesenchymal stem cells derived from human dental pulp (DP-MSCs) and bone marrow (BM-MSCs). Here, we report DP-MSCs exhibit increased osteogenic potential, possess decreased adipogenic potential, form dentin pulp-like complexes, and are resistant to oncogenic transformation when compared to BM-MSCs. Genome-wide RNA-seq and differential expression analysis reveal differences in adipocyte and osteoblast differentiation pathways, bone marrow neoplasm pathway, and PTEN/PI3K/AKT pathway. Higher PTEN expression in DP-MSCs than in BM-MSCs is responsible for the lineage commitment and tumorigenesis differences in both cells. Additionally, the PTEN promoter in BM-MSCs exhibits higher DNA methylation levels and repressive mark H3K9Me2 enrichment when compared to DP-MSCs, which is mediated by increased DNMT3B and G9a expression, respectively. The study demonstrates how several epigenetic factors broadly affect lineage commitment and tumorigenesis, which should be considered when developing therapeutic uses of stem cells.

Increased Plasma Circulating Cell-Free DNA Could Be a Potential Marker for Oral Cancer.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a disease that affects patients worldwide. DNA of dead cells is released into the blood stream and may be isolated from plasma or serum samples. This DNA is termed cell-free DNA (cfDNA). cfDNA is increased in several types of malignancies. We investigated if there was a correlation between cfDNA levels and the progression of OSCC. METHODS: Using quantitative spectrometry, we measured plasma cfDNA in 121 patients with OSCC and 50 matched controls. Mann Whitney and Wilcoxon tests were used to compare differences among various clinical variants. Receiver operating characteristic (ROC) analysis was used to obtain levels suitable for the separation of the clinical subsets. Kaplan-Meier analysis was used to assess correlation with survival. RESULTS: Plasma cfDNA was significantly elevated in patients with OSCC relative to controls. Plasma cfDNA levels correlated with larger tumor size, cervical lymph node metastasis and late stage. Higher plasma cfDNA levels were associated with a poor prognosis of OSCC, which is a new finding. CONCLUSION: Plasma cfDNA could serve as a novel and easily accessible biomarker in OSCC, providing diagnostic and prognostic value.

FAT1 somatic mutations in head and neck carcinoma are associated with tumor progression and survival.

In recent years, the incidence and mortality rates of head and neck squamous cell carcinoma (HNSCC) have increased worldwide. Therefore, understanding genomic alterations in HNSCC carcinogenesis is crucial for appropriate diagnosis and therapy. Protocadherin FAT1, which encodes 4588 amino acid residues, regulates complex mechanisms to promote oncogenesis or suppression of malignancies. Multiplex PCR-based next-generation sequencing (NGS) revealed FAT1 somatic mutations. The clinicopathologic implications of FAT1 in HNSCC were investigated using expression assays, and the functional role of FAT1 in HNSCC pathogenesis was determined using ectopic expression and knockdown experiments. Approximately 29% patients with HNSCC harbored damaging FAT1 mutations. InVEx algorithm identified FAT1 as a significant functional mutation burden. Each type of mutation (missense, nonsense and frameshift) accounted for nearly one-third of deleterious mutations. FAT1 mutations correlated with lower FAT1 expression in tumors. The knockdown of the endogenous expression of FAT1 and exogenous expression of crucial FAT1 domains unequivocally indicated that FAT1 suppressed the migration and invasion capability of HNSCC cells. Functional analysis suggested that nonsense mutations in FAT1 result in the loss of the suppression of tumor progression. FAT1 mutations and downregulation defined nodal involvement, lymphovascular permeation and tumor recurrence. In addition, FAT1 mutations and downregulation are independent predictors of poor disease-free survival in patients with HNSCC. This study is the first to perform multiplex PCR-based NGS to indicate marked non-synonymous FAT1 mutations in HNSCC, which are prognostic indicators. The gene analysis strategy proposed for detecting FAT1 mutations may be a valid method for mutation screening.

ROS-independent ER stress-mediated NRF2 activation promotes warburg effect to maintain stemness-associated properties of cancer-initiating cells.

Cancer-initiating cells (CICs) are responsible for tumor initiation, progression, and therapeutic resistance; moreover, redox homeostasis is important in regulating cancer stemness. Previously, we have identified that cancer cells containing low intracellular reactive oxygen species levels (ROSLow cells) display enhanced features of CICs. However, the specific metabolic signatures of CICs remain unclear and are required for further characterization by systemic screenings. Herein, we first showed CICs mainly relying on glycolysis that was important for the maintenance of stemness properties. Next, we revealed that NRF2, a master regulator of antioxidants, was able to maintain low intracellular ROS levels of CICs, even though in the absence of oxidative stress. We further characterized that NRF2 activation was required for the maintenance of CICs properties. Of ROSLow cells, NRF2 activation not only directly activates the transcription of genes encoding glycolytic enzymes but also inhibited the conversion of pyruvate to acetyl-CoA by directly activating pyruvate dehydrogenase kinase 1 (PDK1) to lead to inhibition of tricarboxylic acid (TCA) cycle; therefore, to promote Warburg effect. A positive regulatory ROS-independent ER stress pathway (GRP78/p-PERK/NRF2 signaling) was identified to mediate the metabolic shift (Warburg effect) and stemness of CICs. Lastly, co-expression of p-PERK and p-NRF2 was significantly associated with the clinical outcome. Our data show that NRF2 acting as a central node in the maintenance of low ROS levels and stemness associated properties of the CICs, which is significantly associated with the clinical outcome, but independent from ROS stress. Future treatments by inhibiting NRF2 activation may exhibit great potential in targeting CICs.

Targeting of miR-31/96/182 to the Numb gene during head and neck oncogenesis.

BACKGROUND: MicroRNAs (miRNAs) play crucial roles in head and neck squamous cell carcinoma (HNSCC). This study investigates whether miR-31, miR-96, and miR-182 are involved in targeting Numb during HNSCC. METHODS: The expression of miR-31/96/182 in tumor tissues was analyzed. Reporter assay, knockdown, expression, and oncogenic analysis were carried out in cell lines. RESULTS: Upregulation of miR-31/96/182 was detected in tumor tissues. In addition, advanced tumors showed higher expression levels of these miRNAs. The expression of these miRNAs was upregulated after treatment with areca ingredients (P < .01 or P < .001). These miRNAs directly targeted the 3' untranslated region (UTR) sequence of the Numb gene. An increased migration and invasion of HNSCC cells was associated with the exogenous expression of miR-31/96/182 (P < .01 or P < .001), and this was reverted by expression of Numb. CONCLUSION: This study provides new evidence demonstrating that there is frequent and concordant upregulation of miR-31, miR-96, and miR-182 during HNSCC and these miRNAs co-target Numb.

Pretreatment pain predicts perineural invasion in oral squamous cell carcinoma: A prospective study.

OBJECTIVES: Perineural invasion (PNI) is an established poor prognostic pathological feature for oral squamous cell carcinoma (OSCC). The purpose of this study was to analyze the role of pretreatment parameters in predicting PNI for OSCC. MATERIALS AND METHODS: We prospectively enrolled into our study 102 newly diagnosed OSCC patients, who were surgically treated from 2011 to 2012. Before treatment, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire H&N35 and the visual analogue scale (VAS) for cancer pain. Pathological examination was performed to ascertain PNI status in all patients. Patients were divided into two groups, those with PNI and without PNI. Pretreatment parameters were compared between the two groups. RESULTS: In univariate analysis, clinical T classification (P<0.001), painkiller use (P=0.001), problem with social eating (P<0.001) and social contact (P=0.002), VAS scores of primary pain (P<0.001) and referred pain (P=0.004) were found to be associated with PNI. Multivariate logistic regression analysis further revealed VAS score of primary pain (P=0.001, OR 2.014) and T3-4 classification (P=0.014, OR 6.422) were independent predictors of PNI. A regression equation incorporating pretreatment pain was developed to predict the probability of having PNI. CONCLUSION: PNI can be predicted by higher pretreatment VAS score of primary pain, as well as more advanced clinical T classification. Careful evaluation of pretreatment pain of primary tumor can thus be helpful in improving treatment decision making for OSCC.

Up-regulation of miR-187 modulates the advances of oral carcinoma by targeting BARX2 tumor suppressor.

Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. Aberrations in miRNA regulation are known to play important roles in OSCC pathogenesis. miR-187 was shown to be up-regulated in head and neck malignancies in our previous screening. This study further investigated the oncogenic potential, clinical implications, and targets of miR-187 in OSCC. We observed that miR-187 increased oncogenicity, particularly migration, of OSCC cells. miR-187 expression increased the xenografic tumorigenicity and metastasis in mice. In addition, metastatic human OSCC had higher miR-187 expression than did non-metastatic tumors. Through vigorous screening, we confirmed BarH-like Homeobox 2 (BARX2) gene as an miR-187 target. BARX2 expression suppressed the migration, invasion, anchorage-independent colony formation, and orthotopic tumorigenesis of OSCC cells. The migratory phenotype and neck metastasis induced by miR-187 was rescued by BARX2 expression. BARX2 expression was down-regulated in the vast majority of OSCC, and this down-regulation was particularly conspicuous in tumors with advanced nodal metastasis. In addition, plasma miR-187 was significantly higher in OSCC patients than in normal individuals. This study highlights the roles of miR-187-BARX2 in driving the carcinogenesis of OSCC. The results suggest that miR-187 is a potential serological marker for OSCC and that targeting of miR-187 might prove effective in attenuating nodal metastasis.

miR-31 targets ARID1A and enhances the oncogenicity and stemness of head and neck squamous cell carcinoma.

miR-31 is oncogenic for head and neck squamous cell carcinoma (HNSCC). Proteins containing the AT-rich interacting domain (ARID) modulate the accessibility of chromatin to the transcription machinery needed for gene expression. In this study, we showed that miR-31 was able to target ARID1A in HNSCC. HNSCC tumors had an inverse miR-31 and ARID1A expression. miR-31 associated oncogenicities were rescued by ARID1A expression in HNSCC cells. Furthermore, ARID1A repressed the stemness properties and transcriptional activity of Nanog/OCT4/Sox2/EpCAM via the protein's affinity for AT-rich sites within promoters. HNSCC patients with tumors having high level of miR-31 expression and high levels of Nanog/OCT4/Sox2/EpCAM expression, together with low level of ARID1A expression, were found to have the worst survival. This study provides novel mechanistic clues demonstrating that miR-31 inhibits ARID1A and that this enriches the oncogenicity and stemness of HNSCC.