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OBJECTIVE: One-third of head and neck squamous cell carcinomas are early-stage oral cavity squamous cell carcinomas (OCSCC). Despite a high curative rate, 20% of early-stage OCSCC patients do not achieve long-term survival. This study evaluates the role of adjuvant therapy (ADJ) in delaying disease progression and prolonging survival. METHODS: This single-institute retrospective cohort study enrolled 481 early-stage OCSCC patients, 16% (78/481) of whom received ADJ. It was reported according to the STROBE guidelines. Cox proportional hazards regression and Kaplan-Meier survival curves were employed to identify suitable candidates for ADJ. RESULTS: The 5-year locoregional recurrence-free survival (LR-RFS) and overall survival rates were 73.2% and 84.9%, respectively. Positive margins and advanced depth of invasion (DOI) were independent predictors of LR-RFS. For patients with positive margins, adjuvant chemoradiotherapy (CRT) was superior to adjuvant radiotherapy alone in improving LR-RFS (hazard ratios for adjuvant CRT vs. none, 0.042; adjuvant radiotherapy alone vs. none, 0.702). Excluding positive margins, advanced DOI was the most critical factor in assessing the need for ADJ. Positive margins and advanced DOI were more appropriate criteria than EORTC 22931/RTOG 9501 for evaluating adjuvant CRT. CONCLUSIONS: Adjuvant CRT was indicated for patients with positive margins and advanced DOI to improve survival outcomes.
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Background/purpose: Though the gold standard method for mandible reconstruction of the defect from segmental mandibulectomy is by osseous flap or graft, using reconstruction plates is still indicated in some cases. Traditionally, the plate is bended immediately after the segmental mandibulectomy by freehand. However, it's difficult to fit well to the original position of mandible, which may result in more complications. This study therefore aimed to investigate whether using prebent plates on computer-aided 3D printing models could reduce the complication rate. Materials and methods: Patients who received mandible reconstruction by reconstruction plate from 2018 to 2022 were enrolled and evaluated in this study. The data, including demographics, indications for surgery, pre-existed preoperative and postoperative therapies, classification of defects, and postoperative outcomes were collected and analyzed. Results: A total of 52 patients were enrolled in our study. The prebent group exhibited a significantly lower complication rate than that of the immediately bent group (P = 0.012). Other risk factors of plate complications included postoperative adjuvant radiotherapy (P = 0.017) and previous surgery (P = 0.047). The complication-free survival rate was also better in the prebent group in a 3-year follow-up period (P = 0.012). Conclusion: Prebent plates on computer-aided printing models proved to be an effective approach to reduce the complications for mandibular reconstruction in segmental mandibulectomy.
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OBJECTIVE: Immune checkpoint inhibitors (ICI) are recommended as the first-line therapy for platinum-refractory head and neck squamous cell carcinoma (HNSCC), a disease with a poor prognosis. However, biomarkers in this situation are rare. The objective was to identify radiomic features-associated biomarkers to guide the prognosis and treatment opinions in the era of ICI. METHODS: A total of 31 platinum-refractory HNSCC patients were retrospectively enrolled. Of these, 65.5% (20/31) received ICI-based therapy and 35.5% (11/31) did not. Radiomic features of the primary site at the onset of recurrent metastatic (R/M) status were extracted. Prognostic and predictive radiomic biomarkers were analysed. RESULTS: The median overall survival from R/M status (R/M OS) was 9.6 months. Grey-level co-occurrence matrix-associated texture features were the most important in identifying the patients with or without 9-month R/M death. A radiomic risk-stratification model was established and equally separated the patients into high-, intermittent- and lower-risk groups (1-year R/M death rate, 100.0% vs. 70.8% vs. 27.1%, p = 0.001). Short-run high grey-level emphasis (SRHGE) was more suitable than programmed death ligand 1 (PD-L1) expression in selecting whether patients received ICI-based therapy. CONCLUSIONS: Radiomic features were effective prognostic and predictive biomarkers. Future studies are warranted.
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BACKGROUND: The multiple symptoms of Sjögren's syndrome lead patients affected by this disease to seek medical advice from different medical disciplines and specialists. Diagnoses are often made many years after initial onset, resulting in mental and physical exhaustion and misunderstandings. PURPOSE: This study was designed to explore the health-seeking experiences of patients with Sjögren's syndrome. METHODS: Qualitative research methods and purposive sampling were used. Fourteen patients with Sjögren's syndrome were interviewed by the first author, and the collected data were analyzed using content analysis. RESULTS: Four themes were revealed from the data, including: (1) distressing symptoms; (2) difficulty in diagnosis; (3) concerns about drug side effects; and (4) facing the disease. The participants initially sought medical attention when they began experiencing early onset symptoms that caused discomfort or annoyance. Their doctors' failure to provide proper diagnoses during the long health-seeking process caused a great deal of suffering to the participants. Although related medications should be taken for life, the participants reported taking lower-than-prescribed dosages out of fear of side-effects. The participants explored their process of coping with the disease, which began with denial and ended with acceptance. By learning from their health-seeking process, participants realized that they needed to take proper care of themselves, adapt to life with their disease, and control related symptoms. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: To facilitate the early diagnosis of Sjögren's syndrome, healthcare professionals should improve their awareness of this condition and refer patients with related symptoms to rheumatologists and immunologists. Effective early diagnosis and treatment can help these patients reduce the time and effort involved in unproductive doctor's visits, allowing them to better continue as productive members of society and to maintain a good quality of life.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Síndrome de Sjögren , Humanos , Calidad de Vida , Síndrome de Sjögren/diagnóstico , Adaptación Psicológica , FatigaRESUMEN
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.
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Carcinoma de Células Escamosas , Liquen Plano Oral , Neoplasias de la Boca , Humanos , Metilación , Estudios de Casos y Controles , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Liquen Plano Oral/genética , Liquen Plano Oral/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Factores de Transcripción de Tipo Kruppel/genéticaRESUMEN
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.
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OBJECTIVE: In approximately 50% of patients with oral cavity squamous cell carcinoma (OCSCC), the disease progresses after curative surgery. However, the role of salvage surgery (SS) is controversial, and life expectancy after SS is unknown. METHODS: In this study, 262 patients with OCSCC with locoregional recurrence and second primary OCSCC were retrospectively enrolled and divided into a resectable (55.0%, 144/262) and unresectable (45.0%, 118/262) groups. After excluding neck recurrence only, SS had been performed 195 times in the resectable group. The corresponding preoperative clinicopathologic factors and postsurgery survival (PSS) of each SS were pooled for analysis. RESULTS: Median survival after disease progression was 64.2 and 10.4â¯months for the resectable and unresectable groups, respectively. In the resectable group, one-fifth (19.5%, 37/190) of the patients died within 1â¯year of SS (PSSâ¯<â¯1â¯year), and one-third (32.8%, 64/195) of the patients had undergone SS two or more times. The interval from the last surgeryâ¯≤â¯12â¯months, depth of invasion of the last surgeryâ¯>â¯1â¯cm, and clinical evidence of nodal disease at the preoperative evaluation were independent predictors of poor PSS. A scoring prediction model was established with 1 point for each factor. The results revealed 1-year postsurgery death rates of 10.3% in the low-risk group (score: 0-1) and 48.6% in the high-risk group (score: 2 or 3) (Pâ¯<â¯0.001). CONCLUSIONS: In conclusion, an effective scoring model predicting life expectancy after SS for patients with OCSCC was established.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Carcinoma de Células Escamosas/patología , Humanos , Neoplasias de la Boca/patología , Recurrencia Local de Neoplasia/patología , Estudios Retrospectivos , Terapia Recuperativa/métodos , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Background/purpose: Oral cancer has been recognized as one of the most common malignancies worldwide and ranks the fifth leading cause of cancer death in Taiwan. A variety of studies have demonstrated that microRNAs are involved in the regulation of the hallmarks of oral carcinogenesis. Nevertheless, the effect of miR-1266-5p on the tumorigenesis of oral cancer has not been investigated, and not to mention, its functional role in oral cancer. Materials and methods: The upregulation of miR-1266-5p in SASVO3 and SASM5 cells was identified by RNA-Seq and examined by qRT-PCR analysis. The phenotypic assays including proliferation activity, migration capacity, invasion, wound healing, and colony-forming abilities were conducted in oral cancer cells after knockdown of miR-1266-5p. Luciferase reporter and western blotting were used to validate DAB2IP was a direct target of miR-1266-5p in oral cancer. Results: We identified that miR-1266-5p was significantly overexpressed in highly tumorigenic SASVO3 cells and metastatic SASM5 cells. qRT-PCR revealed that miR-1266 significantly increased upregulated in oral cancer and lymph node metastatic tissues compared to normal counterparts We found that downregulation of miR-1266-5p inhibited the proliferation and clonogenicity capacities of SASVO3 cells. Knockdown of miR-1266-5p also inhibited migration/invasion and self-renewal abilities in SASM5 cells. Moreover, we validated miR-1266-5p directly bound to the 3'UTR of DAB2IP in oral cancer cells. We found that DAB2IP knockdown reversed the inhibitory effects of self-renewal and migration mediated by silencing of miR-1266-5p. Conclusion: miR-1266 functions as a biomarker in oral cancer patients, and downregulation of miR-1266 may ameliorate the oncogenic and metastasis potential of oral cancer by targeting DAB2IP.
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BACKGROUND/PURPOSE: Cancer stem cells (CSCs) have been known to be implicated in tumorigenesis, metastasis, and drug resistance in oral squamous cell carcinomas (OSCC). In this study, we aimed to investigate whether magnolol, a polyphenolic component derived from Magnolia officinalis, exhibited the anti-CSCs properties. METHODS: The cytotoxicity of magnolol was tested using normal gingival epithelioid SG cells and sphere-forming OSCC-CSCs isolated from SAS, OECM1, and GNM cells. Secondary sphere-forming ability, the proportion of ALDH1 positive cells, Transwell migration, and invasion capacities were examined as well. The chemosensitive effects of magnolol were investigated using MTT, secondary sphere-forming, and invasion assays. RESULTS: Magnolol exerted a higher cytotoxicity of OSCC-CSCs and cancer stemness features, including self-renewal ability, the expression CSC marker, migration, and invasion capacities were all downregulated in magnolol-treated OSCC-CSCs. Moreover, administration of magnolol potentiated the effect of cisplatin, including a decrease in cell viability, self-renewal, and invasion activities. In addition, we observed that the secretion of IL-6 and phosphorylation of Stat3 were decreased in OSCC-CSCs treated with magnolol. CONCLUSION: Our data suggest that magnolol is able to target CSCs and suppress the cancer stemness properties, at least in part, via IL-6/Stat3 signaling. Besides, a dietary supplement of magnolol may function as an adjunct to cisplatin treatment.
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Compuestos de Bifenilo/farmacología , Interleucina-6 , Factor de Transcripción STAT3/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Línea Celular Tumoral , Humanos , Interleucina-6/metabolismo , LignanosRESUMEN
BACKGROUND/PURPOSE: Oral submucous fibrosis (OSF) a well-recognized oral premalignant disorder. Several studies have demonstrated that periostin, a matricellular protein, is involved in the development and pathogenesis of fibrosis diseases. Nevertheless, the contribution of periostin in OSF remains to be uncovered. The purpose of the study was to illustrate the functional role of periostin involved in OSF pathogenesis. METHODS: RNA-sequencing was employed to screen for differentially expressed genes in normal and OSF tissues. Validation of the upregulation of periostin in OSF specimens and fibrotic buccal mucosal fibroblasts (fBMFs) was conducted by qRT-PCR. The correlation of the gene expression of periostin and various fibrosis markers was analyzed. In addition, the functional role of periostin in myofibroblast features was tested using collagen gel contraction and transwell migration assays. RESULTS: We observed overexpression of periostin in OSF specimens using RNA-sequencing and confirmed its upregulation in OSF tissues and patient-derived fBMFs. Besides, there was a positive relationship between the expression of periostin and several fibrosis-associated markers, including ACTA2 (α-smooth muscle actin; α-SMA), COL1A1 (type 1 collagen α1 chain), TGFB1 (TGF-ß1), and FN1 (fibronectin). Furthermore, we examined the effect of silencing periostin on the maintenance of myofibroblast characteristics and showed that knockdown of periostin suppressed the expression of α-SMA. Also, inhibition of periostin markedly downregulated the myofibroblast activities (collagen gel contraction and migration capacities). CONCLUSION: Our results indicate the aberrant expression of periostin in OSF tissues and myofibroblasts. Moreover, the expression of periostin is positively associated with fibrosis markers, and repression of periostin may be a promising direction to alleviate the progression of OSF.
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Miofibroblastos , Fibrosis de la Submucosa Bucal , Transdiferenciación Celular , Fibroblastos , Fibrosis , Humanos , Mucosa Bucal/patología , Fibrosis de la Submucosa Bucal/genética , Fibrosis de la Submucosa Bucal/patologíaRESUMEN
Patients with oral cavity squamous cell carcinoma (OCSCC) who develop distant metastasis (DM) face poor outcomes, and effective prediction models of DM are rare. A total of 595 patients with OCSCC were retrospectively enrolled in this study. Because pathological N staging significantly influences the development and mechanisms of DM, the patients were divided into nodal-negative (pN-) and -positive (pN+) groups. Clinical outcomes, prognoses, and prediction models were analyzed separately for both groups. Overall, 8.9% (53/595) of these patients developed DM. Among the DM cases, 84.9% (45/53) of them developed DM within the first 3 years. The median overall survival, locoregional recurrence-free survival, time until DM development, and postmetastatic survival were 19.8, 12.7, 14.6, and 4.1 months, respectively. Distinguishing patients who only developed locoregional recurrence from those with DM according to locoregional conditions was difficult. Age, surgical margin, and early locoregional recurrence were predictors of DM that were independent of time until DM in the pN- group; the lymphocyte-to-monocyte ratio, presence of lymphovascular invasion, and early locoregional recurrence in the pN+ group were determined. If one point was scored for each factor, then two scoring systems were used to classify the patients into low- (score = 0), intermittent- (score = 1), or high- (score = 2 or 3) risk for the pN- and pN+ groups. According to this scoring system, the 3-year DM rates for the low, intermittent, and high risk subgroups were 0.0%, 5.9%, and 17.8% for the pN- group and 7.1%, 44.9%, and 82.5% for the pN+ group, respectively. These systems also effectively predicted DM, and the areas under the curve predicted DM occurring within the first 3 years were 0.744 and 0.820 for the pN- and pN+ groups, respectively. In conclusion, effective scoring models were established for predicting DM.
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Dysbiosis of oral microbiome may dictate the progression of oral squamous cell carcinoma (OSCC). Yet, the composition of oral microbiome fluctuates by saliva and distinct sites of oral cavity and is affected by risky behaviors (smoking, drinking and betel quid chewing) and individuals' oral health condition. To characterize the disturbances in the oral microbial population mainly due to oral tumorigenicity, we profiled the bacteria within the surface of OSCC lesion and its contralateral normal tissue from discovery (n = 74) and validation (n = 42) cohorts of male patients with cancers of the buccal mucosa. Significant alterations in the bacterial diversity and relative abundance of specific oral microbiota (most profoundly, an enrichment for genus Fusobacterium and the loss of genus Streptococcus in the tumor sites) were identified. Functional prediction of oral microbiome shown that microbial genes related to the metabolism of terpenoids and polyketides were differentially enriched between the control and tumor groups, indicating a functional role of oral microbiome in formulating a tumor microenvironment via attenuated biosynthesis of secondary metabolites with anti-cancer effects. Furthermore, the vast majority of microbial signatures detected in the discovery cohort was generalized well to the independent validation cohort, and the clinical validity of these OSCC-associated microbes was observed and successfully replicated. Overall, our analyses reveal signatures (a profusion of Fusobacterium nucleatum CTI-2 and a decrease in Streptococcus pneumoniae) and functions (decreased production of tumor-suppressive metabolites) of oral microbiota related to oral cancer.
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Disbiosis/inmunología , Detección Precoz del Cáncer/métodos , Microbiota/inmunología , Mucosa Bucal/microbiología , Neoplasias de la Boca/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Adulto , Anciano , Estudios de Cohortes , ADN Bacteriano/aislamiento & purificación , Progresión de la Enfermedad , Disbiosis/diagnóstico , Disbiosis/microbiología , Disbiosis/patología , Fusobacterium nucleatum/genética , Fusobacterium nucleatum/inmunología , Fusobacterium nucleatum/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Mucosa Bucal/inmunología , Mucosa Bucal/patología , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/microbiología , Neoplasias de la Boca/patología , Pronóstico , ARN Ribosómico 16S/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/microbiología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/inmunología , Streptococcus pneumoniae/aislamiento & purificación , Microambiente Tumoral/inmunologíaRESUMEN
OBJECTIVES: Early progression, defined as a disease-free interval (DFI) of less than 6 months after completion of adjuvant platinum-based chemoradiotherapy (CRT), leads to poor outcomes in locally advanced oral cavity squamous cell carcinoma (OCSCC). However, appropriate biomarkers for predicting early progression remain unknown. METHODS: In this study, 346 patients with OCSCC, who underwent curative surgical resection and platinum-based adjuvant CRT at the Taipei Veterans General Hospital (202 patients, training cohort) and Chung Shan Medical University Hospital (144 patients, validation cohort) were enrolled. The clinical-pathological variables were compared using the χ2 test. Cox proportional-hazards analyses were performed for DFIs. Survival was estimated using the Kaplan-Meier method and log-rank tests, and a scoring system for predicting early progression was established. RESULTS: One-fifth (20.5%, 71/346) of all patients experienced progression within 6 months. Each of the independent factors for the DFI in the training cohort, including pT3-4, extracapsular spread, and perineural invasion, were assigned a score of one point to establish a scoring system. The 6-month DFIs of the low-risk (score 0-1), intermediate-risk (score 2), and high-risk (score 3) groups were 97.8%, 78.7%, and 35.7% and 88.2%, 77.6%, and 42.1% in the training and validation cohorts, respectively. If the cutoff level was ≥2 or <2, the sensitivity/specificity/area under the curve for the training and validation cohorts were 94.4%/56.1%/0.837, and 73.3%/56.6%/0.703, respectively. CONCLUSIONS: The established scoring system effectively predicted early progression after adjuvant CRT for locally advanced OCSCC.
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Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/cirugía , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugía , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia Adyuvante/métodos , Progresión de la Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/terapia , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Platino (Metal)/uso terapéutico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Análisis de SupervivenciaRESUMEN
BACKGROUND/PURPOSE: Oral cancer stem cells (CSCs) have been considered as the key cells that are implicated in tumor recurrence and metastasis. In recent years, great attention has been paid to the significance of various non-coding RNAs due to their regulatory roles in oral CSCs. Although the function of long non-coding RNA MEG3 in various cancers has been investigated, its effects on the features of oral CSCs remained to be determined. METHODS: The expression levels of MEG3 in tongue squamous cell carcinomas and prognostic effect have been evaluated. We assessed the expression of MEG3 in sphere cells (oral CSCs) using qRT-PCR. Secondary sphere formation and invasion assays were conducted to evaluate the self-renewal and metastatic abilities, respectively. Bioinformatics software and luciferase reporter assay were used to predict and verify the relationship between MEG3 and miR-421. RESULTS: MEG3 was downregulated in the tissues of oral cancer and associated with a poor prognosis. In oral CSCs, the expression of MEG3 was repressed and overexpression of MEG3 resulted in suppression of self-renewal and invasion abilities. Luciferase reporter assay showed that miR-421 directly interacted with MEG3, and our subsequent experiment demonstrated that elevation of miR-421 reversed the MEG3-inhibited characteristics of oral CSCs. CONCLUSION: Our findings suggest that MEG3 can serve as a tumor suppressor in oral CSCs by impeding the action of miR-421. Moreover, targeting MEG3-miR-421 axis has the potential to mitigate the tumor recurrence and metastasis.
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MicroARNs , ARN Largo no Codificante , Línea Celular Tumoral , Proliferación Celular , Humanos , MicroARNs/genética , Recurrencia Local de Neoplasia , Células Madre Neoplásicas , ARN Largo no Codificante/genéticaRESUMEN
Oral submucosal fibrosis (OSF) is a premalignant disorder of the oral cavity, and areca nut chewing is known to be a major etiological factor that could induce epithelial to mesenchymal transition (EMT) and activate buccal mucosal fibroblasts (BMFs). However, this detailed mechanism is not fully understood. In this study, we showed that the upregulation of Snail in OSF samples and fibrotic BMFs (fBMFs) may result from constant irritation by arecoline, a major alkaloid of the areca nut. The elevation of Snail triggered myofibroblast transdifferentiation and was crucial to the persistent activation of fBMFs. Meanwhile, Snail increased the expression of numerous fibrosis factors (e.g., α-SMA and collagen I) as well as IL-6. Results from bioinformatics software and a luciferase-based reporter assay revealed that IL-6 was a direct target of Snail. Moreover, IL-6 in BMFs was found to further increase the expression of Snail and mediate Snail-induced myofibroblast activation. These findings suggested that there was a positive loop between Snail and IL-6 to regulate the areca nut-associated myofibroblast transdifferentiation, which implied that the blockage of Snail may serve as a favorable therapeutic strategy for OSF treatment.
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Oral submucous fibrosis (OSF) is an oral precancerous condition associated with the habit of areca nut chewing and the TGF-ß pathway. Currently, there is no curative treatment to completely heal OSF, and it is imperative to alleviate patients' symptoms and prevent it from undergoing malignant transformation. Arctigenin, a lignan extracted from Arctium lappa, has been reported to have a variety of pharmacological activities, including anti-fibrosis. In the present study, we examined the effect of arctigenin on the cell proliferation of buccal mucosal fibroblasts (BMFs) and fibrotic BMFs (fBMFs), followed by assessment of myofibroblast activities. We found that arctigenin was able to abolish the arecoline-induced collagen gel contractility, migration, invasion, and wound healing capacities of BMFs and downregulate the myofibroblast characteristics of fBMFs in a dose-dependent manner. Most importantly, the production of TGF-ß in fBMFs was reduced after exposure to arctigenin, along with the suppression of p-Smad2, α-smooth muscle actin, and type I collagen A1. In addition, arctigenin was shown to diminish the expression of LINC00974, which has been proven to activate TGF-ß/Smad signaling for oral fibrogenesis. Taken together, we demonstrated that arctigenin may act as a suitable adjunct therapy for OSF.
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Furanos/administración & dosificación , Lignanos/administración & dosificación , Miofibroblastos/efectos de los fármacos , Fibrosis de la Submucosa Bucal/tratamiento farmacológico , Factor de Crecimiento Transformador beta/genética , Areca/química , Arecolina/química , Movimiento Celular/efectos de los fármacos , Transdiferenciación Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Mucosa Bucal/efectos de los fármacos , Miofibroblastos/metabolismo , Fibrosis de la Submucosa Bucal/genética , Fibrosis de la Submucosa Bucal/patología , Proteína Smad2/genética , Factor de Crecimiento Transformador beta/biosíntesisRESUMEN
Epithelial-mesenchymal transition (EMT) has been implicated in fibrogenesis and carcinogenesis; however, the exact role of EMT-inducer Slug in the progression of precancerous oral submucous fibrosis (OSF) has not been investigated. In the current study, we showed that the expression of Slug was upregulated in OSF tissues and associated with various myofibroblast markers. After silence of Slug in fibrotic buccal mucosal fibroblasts (fBMFs), the elevated myofibroblast activities and fibrosis markers were all downregulated. Our data revealed that arecoline, an areca nut alkaloid, increased the expression of Slug in normal BMFs, and inhibition of Slug successfully prevented the arecoline-induced myofibroblast activation. Additionally, overexpression of Slug in BMFs stimulated the activities of myofibroblasts, indicating that upregulation of Slug by arecoline contributes to the myofibroblast transdifferentiation. Most importantly, Slug was able to bind to the E-box of type I collagen, leading to increased expression of type I collagen. Altogether, this study demonstrated the abnormal elevation of Slug in OSF and its significance in arecoline-induced fibrogenesis. Moreover, downregulation of Slug could be a potential target for OSF remedy via suppression of myofibroblast activities and type I collagen.