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Whether oral lichen planus (OLP) was potentially malignant remains controversial. Here, we examined associations of ZNF582 methylation (ZNF582This is a case-control study. ZNF582OLP lesions showed significantly lower ZNF582OLP is unlikely to be potentially malignant based on ZNF582

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

Background MicroRNAs (miRNAs) are short, noncoding RNAs that inhibit the expression of target genes that play roles in tumorigenesis. MiR-21, miR-31, and miR-184 are oncogenic miRNAs for head and neck squamous cell carcinoma (HNSCC). Factor-inhibiting hypoxia (FIH)-inducible factor is known to inactivate hypoxia-induced downstream effectors and is involved in HNSCC suppression. This study investigates whether miR-21, miR-31, and miR-184 target FIH in HNSCC. Methods Reporter assays, Western blot analysis, quantitative reverse transcriptase-polymerase chain reaction (PCR) analysis, and phenotypic assays were used to prove that miR-21, miR-31, and miR-184 directly target FIH. Clinicopathological implications of the gene expression were also analyzed. Results MiR-21, miR-31, and miR-184 directly bind to various sites in the 3′ untranslated region (UTR) of FIH transcript, and this binding is associated with decreased FIH protein expression in HNSCC cells. Treatment with the precursors of these miRNAs increases the proliferation and migration of HNSCC cells. Concomitant treatment with precursors repressed FIH and enhanced oncogenicity most profoundly. Upregulation of miR-21, miR-31, and miR-184 expression is found in more than 80% of HNSCC tumors and 72% of tumors have concordant upregulation of these 3 oncogenic miRNAs. The highest expression of these miRNAs is present in T4b and stage IVB tumors. Downregulation of FIH mRNA expression is noted in 69% of HNSCC tumors, and in tumors exhibiting high expression of these miRNAs, the FIH mRNA expression is consistently downregulated. Conclusion This study provides novel clues indicating that miR-21, miR-31, and miR-184 co-target FIH tumor suppressor during pathogenesis in the vast majority of HNSCC. © 2014 Wiley Periodicals, Inc. Head Neck, 2015

Head and neck squamous cell carcinoma (HNSCC) is a prevalent disease worldwide, and the survival of HNSCC has not improved significantly over the last few decades. MicroRNAs (miRNAs) have an important regulatory role during carcinogenesis. Our study investigated the pathogenic implications of miR-134 in head and neck carcinogenesis. The clinicopathologic implications of miR-134 in HNSCC were investigated using expression assays and the functional role of miR-134 in HNSCC pathogenesis was determined using ectopic expression, knockdown and reporter assay experiments. Xenographic tumorigenesis and orthotopic nodal metastasis were assayed in mouse models. In situ hybridization and immunohistochemistry were used to detect the expression of miR-134 and the WWOX gene in human HNSCC. The results indicated that miR-134 was upregulated in HNSCC tissues relative to control mucosa. High expression of miR-134 was associated with nodal metastasis and mortality of patients. Decreased plasma miR-134 levels after tumor ablation indicated a better prognosis for patients. Multivariate analysis showed that high miR-134 expression in HNSCC was an independent predictor of poor survival. Ectopic miR-134 expression significantly enhanced in vitro oncogenic phenotypes and the orthotopic growth and metastasis of HNSCC cells. miR-134 targeted WW domain-containing oxidoreductase (WWOX) gene and cell invasion enhanced by miR-134 expression was abrogated by ectopic WWOX expression in HNSCC cells. miR-134 expression was reversely associated with the WWOX expression in HNSCC tissues. Evidences from our study substantiated that miR-134 expression contributes to head and neck carcinogenesis by targeting the WWOX.

Background This study elucidated the association between histopathological factors and the prognosis of oral carcinoma. As the histopathological factors were determined from the surgical specimen and this can only be used for the choices of postoperative regimens, this study also investigated the linkage between prognostic factors and the expression of key molecules to examine the feasibility of markers as predictors. Methods Clinicopathological factors of 101 oral carcinomas were cross-analyzed with disease-free survival. The expression of nerve growth factor (NGF) and its receptor, tyrosine kinase A receptor, was assayed with immunohistochemistry. Results Nodal metastasis was the most crucial clinical predictor for disease-free survival. Perineural invasion (PNI) was an independent histopathological predictor for both nodal metastasis (P = 0.004) and disease-free survival (P = 0.019). Patients with advanced tumor and PNI exhibited the high hazard for tumor progression and poor disease-free survival. NGF immunoreactivity in tumors was correlated with PNI (P = 0.005) and neck lymph node metastasis (P = 0.036). Conclusion Perineural invasion is the indicator of worst prognosis. As NGF immunoreactivity was found to be associated with PNI and nodal metastasis, the NGF immunoreactivity of oral carcinoma revealed by diagnostic biopsy suggests that alternative therapeutic approaches might be appropriate.

Objectives In this study, we examined the role of p16INK4A, a surrogate biomarker of HPV-related head and neck cancers with better prognosis, in an endemic area of betel quid (BQ)-related oral squamous cell carcinoma (OSCC). Methods p16INK4A immunohistochemistry was examined in 165 OSCCs, statistical analyses were performed to elucidate the correlation between p16INK4A expression and BQ habits/pathologic features, and the prognostic impact of p16INK4A and different parameters were analyzed. Results The incidence of p16INK4A expression was similar between BQ chewers and non-chewers. p16INK4A expression was significantly associated with nodal metastasis (P = 0.005). There was a trend suggesting that the loss of p16INK4A expression was more frequent in higher T stages, however, this was found only in patients without lymph node metastasis (P = 0.059). A poorer prognosis and a higher risk of tumor recurrence were found in OSCCs without p16INK4A expression. (The HR for cancer-specific mortality and cancer recurrence was 3.55 and 1.89, respectively.) Conclusion Although it has been suggested that BQ chewers had a greater tendency toward tumor recurrence and poor outcome, our data demonstrated that p16INK4A expression is unrelated to BQ habit and that p16INK4A downregulation is a strong predictor for OSCC progression, recurrence and survival in Taiwan. J. Surg. Oncol. 2012; 106:149–154. © 2012 Wiley Periodicals, Inc.

Toensurequalitycontrolandassuranceintissueengineering,noninvasive,real-timeandasepticevaluationofcell-baseddevices is required before product release. In this study, Raman spectroscopy was applied to monitor the cellular activities of an oral mucosa equivalent (EVPOME) produced exvivo from cultured autogenous oral keratinocytes and acellular dermis – AlloDerm. Raman spectra showed a positive correlation of the peak area ratio of amide I (1655 cm −1 )/phenylalanine (1004 cm −1 )w ith a negative linear regression (R 2 > 0.95) according to the number of cultured days, especially on the 14thand21st day. This work demonstrates the successful application of Raman spectroscopy for quantitatively monitoring and evaluating the maturity of EVPOME. Copyright c � 2010 John Wiley & Sons, Ltd.

MicroRNA-200c (miR200c) is emerging as an important regulator of tumourigenicity and cancer metastasis with a strong capacity for inducing epithelial-mesenchymal transitions. However, the role of miR200c in head and neck squamous cell carcinoma (HNSCC) and HNSCC-associated cancer stem cells (HNSCC-CSCs) is unknown. In this study, the expression of miR200c in the regional metastatic lymph node of HNSCC tissues was significantly decreased, but BMI1 expression was increased as compared to parental tumours. Importantly, site-directed mutagenesis with a luciferase reporter assay showed that miR200c targeted the 3' UTR of BMI1 in HNSCC cells. Isolated HNSCC-derived ALDH1(+) /CD44(+) cells displayed CSC-like tumour initiating and radio-resistant properties. The expression levels of miR200c were significantly down-regulated while BMI1 was increased in HNSCC-ALDH1(+) /CD44(+) compared to the other subsets of HNSCC cells. Furthermore, increased miR200c expression or knockdown of BMI1 could significantly inhibit the malignant CSC-like properties of ALDH1(+) /CD44(+) cells. miR200c over-expression further down-regulated the expressions of ZEB1, Snail and N-cadherin, but up-regulated E-cadherin expression in ALDH1(+) /CD44(+) cells. Finally, a xenotransplantion study confirmed that over-expression of miR200c or BMI1 knockdown effectively inhibited the lung metastatic ability and prolonged the survival rate of ALDH1(+) /CD44(+) -transplanted mice. In summary, miR200c negatively modulates the expression of BMI1 but also significantly inhibits the metastatic capability of epithelial-mesenchymal transitions in malignant HNSCC by reducing the expression of BMI1/ZEB1. Restoration of miR200c in HNSCC and CSCs may be a promising therapeutic approach.

Oral Diseases (2010) 16, 360–364 Backgrounds: Oral squamous cell carcinoma (OSCC) is a worldwide disease. MicroRNAs are endogenously expressed non-coding RNAs that have important biological and pathological functions. miR-31 was found markedly up-regulated in OSCC and several other malignancies. However, miR-31 expression was also down-regulated in the metastasis process of breast carcinoma. Materials and methods: Using quantitative RT-PCR analysis, we identified plasma miR-31 in OSCC patients (n = 43) and case controlled individuals (n = 21). Nine OSCC patients saliva were also analyzed. The Mann–Whitney test and Wilcoxon matched pairs test were used to compare the differences among the various clinical variants. Results: miR-31 in plasma was significantly elevated in OSCC patients relative to age and sex-matched control individuals. This marker yielded a receiver operating characteristic curve area of 0.82 and an accuracy of 0.72 defined by leave-one-out cross-validation. In addition, the plasma miR-31 in patients was remarkably reduced after tumor resection suggesting that this marker is tumor associated. Our preliminary analysis also demonstrated the feasibility of detecting the increase of miR-31 in patient’s saliva. Conclusion: This study concluded that plasma miR-31 could be validated a marker of OSCC for diagnostic uses.

Head and neck squamous cell carcinoma (HNSCC) is a global malignancy. The insulin-like growth factor (IGF) signalling axis plays a critical role in tumourigenesis. This study defined the clinical and functional roles of insulin-like growth factor binding protein-5 (IGFBP-5) in HNSCC. Down-regulation of IGFBP-5 mRNA expression was found during the progression from pre-cancer to HNSCC. The down-regulation in HNSCC was associated with a higher propensity to nodal metastasis. SAS and OECM-1 are HNSCC cells that do, or do not, express IGFBP-5, respectively. Recombinant IGFBP-5 reduced the proliferation of OECM-1 cells and this was exerted mainly through blockade of the IGF pathways. Either IGFBP-5 or IGF-I treatment alone promoted OECM-1 migration, but a combination of treatments generated antagonistic effects. Overexpression of IGFBP-5 reduced the proliferation and anchorage-independent growth of both OECM-1 and SAS cells. Conversely, knockdown of IGFBP-5 expression significantly induced the proliferation and anchorage-independent growth of SAS cells. It also induced the growth of xenografted SAS tumours. SAS transfectants that expressed mutant or truncated IGFBP-5, which lack IGF binding activity, exhibited significantly lower anchorage-independent growth than vector control. This suggests that IGFBP-5 possesses an IGF-independent suppressor function. The suppressive effects of IGFBP-5 on the tumourigenesis of HNSCC might be invaluable to future neoplastic intervention.

Background: Circulating matrix metalloproteinase-9 (MMP-9) is a prognostic factor for gastric cancer and vascular diseases, and has been associated with head and neck cancers. The −1562 C-to-T polymorphism in MMP-9 promoter (abbreviated MMP-9−1562 C>T polymorphism) leads to differential transcription, and is associated with increased susceptibility to neoplastic and vascular diseases. Thus, our aim was to determine whether a functional MMP-9 polymorphism might also influence the risk or affect the progression of areca-associated oral cancers. Methods: Genomic DNAs were obtained from peripheral blood cells of male subjects with areca-associated oral squamous cell carcinoma (OSCC) (n = 192), oral submucosal fibrosis (OSF) (n = 73), and non-diseased areca users (n = 191). The PCR-based restriction fragment length polymorphism analysis was performed for MMP-9 genotyping. Results: MMP-9−1562 C>T polymorphism was not associated with the risk of OSCC or OSF. However, when subjects were stratified by the median age, an association with the risk of OSCC was found in younger patients (P = 0.029). The T allele frequency was significantly higher in the subset of older patients with buccal mucosa OSCC than older patients with OSCC in counterpart locations. The joint MMP-9−1562 C>T and MMP-3−1171 5A>6A functional polymorphisms were not associated with OSCC risk or patient survival. Conclusion: Aberrant MMP-9 expression is closely related to tumor invasiveness and the prognosis of head and neck cancers. However, functional MMP-9−1562 C>T polymorphism is associated with OSCC risk only in younger areca chewers. The impact of aging or areca-related effect on this functional polymorphism should be elucidated.

Background: The main cause of treatment failure in resectable oral squamous cell carcinoma (OSCC) is metastasis. E-cadherin (E-cad) plays a principal role in cell adhesion and motility, and is associated with OSCC progression. The aim of this study was to investigate the clinical significance of E-cad expression in OSCC with lymph node metastasis which had radical neck dissection done. Method: Immunohistochemistry was used to detect E-cad expression in normal oral mucosa (NOM) (n = 10), oral precancerous lesions (OPLs) (n = 20), primary OSCC (n = 45), and their paired metastatic lesions (n = 45). E-cad immunoreactivity correlated with the clinicopathologic features. Results: E-cadherin immunoreactivity was progressively reduced in the NOM followed by OPLs and primary OSCC (58%). It decreased significantly in the advanced stages of OSCC. However, the increase in E-cad immunoreactivity was observed in the majority (60%) of metastatic lesions in relation to primary OSCC. Patients with such increased or positive immunoreactivity of E-cad in metastatic lesions exhibited worse prognosis. Conclusion: The findings suggested a dynamic change in E-cad immunoreactivity during tumorigenesis and metastasis of OSCC. In a multivariate analysis, E-cad immunoreactivity in metastasis lesions (odds ratio 3.74, 95% CI 1.15–14.67; P = 0.040) implied the potential role of mortality predictors for OSCC cases with nodal involvement.

Background: The increased expression of Cav-1 is seen in various cancers from prostate, esophagus, colon, breast and pancreas yet the information regarding the correlation between the expression of Cav-1 and oral cancer is blind. Thus, the expression profile of caveolin-1 (Cav-1) in oral carcinogenesis and the correlation to the clinicopathologic covariates are examined in this study. Methods: Immunohistochemistry was used to detect Cav-1 expression in non-cancerous matched tissues (NCMT; n = 12), and tissue from normal oral mucosa (NOM; n = 12), oral pre-cancer lesions (OPL; n= 17), primary oral squamous cell carcinoma (POSCC; n = 47) and metastatic OSCC (MOSCC; n = 8). The Cav-1 expression was correlated to the age, site, areca use, stage, size, nodal involvement, and differentiation stage. Western blot was used to confirm the specificity of antibody and to follow changes in Cav-1 expression. Results: The Cav-1 immunoreactivity increased significantly from 8% in NOM and 17% in NCMT to 53% in OPL and 79% in POSCC. In addition, lymph node metastasis (LNM) was present in 62% of Cav-1(+) POSCCs, but only in 10% of Cav-1(–) POSCCs. Remarkably, only 38% of MOSCCs had Cav-1 immunoreactivity. Conclusion: An increased Cav-1 expression is seen in the stepwise carcinogenesis from NOM, NCMT, OPL to POSCC. The decrease in expression from the POSCC to MOSCC indicates the value to explore its biphasic functions in oral carcinogenesis. Whether Cav-1 is an important predictor or prognosis for survival still awaits the extension of clinical follow-up.

Background: The importance of the CYP1A1 polymorphisms at exon 7 (Ile/Val) and 3′-untranslated region (3′-UTR) has been controversial in oral squamous cell carcinoma (OSCC) or head and neck SCC (HNSCC) denoting the value of exploring the correlation between these polymorphisms and risk of betel/smoking associated OSCC. It is also important to evaluate the association between CYP1A1 polymorphisms and susceptibility of oral precancerous lesion (OPL) to confirm the findings in OSCC cases. Methods: We examined polymorphic prevalence of CYP1A1 at exon 7 (Ile/Val) and 3′-UTR in 106 cases with OSCC, 60 cases with OPL, and 146 controls. DNA isolated from surgical specimens and whole blood was used for PCR-based genotyping. Results: The prevalence of the CYP1A1 A/G genotype (Ile/Val) and G/G genotype (Val/Val) in exon 7 of cases with OSCC (79.2 and 7.6%) and OPL (68.3 and 10%) were significantly higher than in controls (53.4 and 1.4%) (P

BACKGROUND Within the abundant retinoids nuclear receptors, abnormally low expression of the RAR-beta has been shown to contribute to neoplastic progression in oral epithelium in western countries. Distinctly different risk factors contributing to oral squamous cell carcinoma (OSCC) in epidemiologically different societies denote the value of exploring the role of RAR-beta expression in OSCC associated with betel quid (BQ) use in our society. METHODS We examined the cellular expression of RAR-beta using in situ hybridization (ISH) analysis on 38 pairs of surgical specimens of primary OSCC and non-cancerous matched tissues (NCMT) to correlate with their clinico-pathological features including age, sites of tumor, habit of BQ use, stage, size of primary tumor, lymph node metastasis, differentiation. RESULTS Of all cases analyzed, BQ users were significantly younger than non-BQ users (51.2 +/- 2.1 vs. 60.2 +/- 2.6, P = 0.01). 52% OSCC of BQ users (13/25) and 23% OSCC of non-BQ users (3/13) exhibited the absence of RAR-beta expression. In 17 paired-samples from buccal mucosa (BM), most NCMT and less than half of OSCC exhibited RAR-beta expression (16/17, 94% vs. 8/17, 47%, P = 0.003). The RAR-beta expression was seen in the vast majority of the well-differentiated OSCC and in less than half of the moderately differentiated OSCC only (15/20, 75% vs. 7/18, 39%, P = 0.03). CONCLUSION A correlation between the loss of RAR-beta expression and more advanced histopathological grade tumors was observed. This study also suggests that the loss of RAR-beta expression is significant in BM OSCC, which preferentially occurs in BQ users.

To determine the alterations of the FHIT (fragile histidine triad) gene in oral squamous cell carcinoma (OSCC), this study examined mutation, promoter methylation, mRNA transcription, and protein expression of FHIT in OSCC associated mostly with the use of betel and/or tobacco. Analyses of the coding exons (exons 5–9) identified a deletion of one base in intron 4 in one tumour and a deletion of exon 7 in two tumours. Using bisulphite genomic sequencing, 28% of theinformative subjects exhibited promoter methylation. An aberrant FHIT transcript spanning from exon 3 to exon 10, which was verified by RT-PCR analysis, was identified in 36% of the OSCC subjects, 50% of the oral pre-invasive lesions, and 5% of the non-cancerous match tissue.An abnormal immunohistochemical level of Fhit was detected in 41% of OSCC subjects. Astatistically significant association was found between aberrant transcription of the FHIT geneand an abnormal level of Fhit immunoreactivity. The results indicated that alteration ofFHIT is a frequent occurrence in OSCC and thus suggests that the aberrance in FHIT transcription could be an early event of oral carcinogenesis. Copyright © 2002 John Wiley & Sons, Ltd.

Oral squamous cell carcinoma (OSCC) is one of the most commonly diagnosed cancers worldwide. Chromosome 20q is a hotspot for gene amplification in OSCC and the serine/threonine kinase STK15 (also named Aurora-A) maps to 20q13. The amplification and over-expression of STK15 is common in neoplasia but the functional and clinical impact of STK15 in OSCC remains poorly understood. STK15 copy number is amplified in 12% of OSCCs and nuclear STK15 protein expression increases with tumour progression. In vivo elevated nuclear STK15 protein expression is significantly associated with the worse prognosis of OSCC patients. The combination of high nuclear STK15 and Ki-67 expression has a 2.55-fold hazard for cancer-associated mortality. In vitro knockdown of STK15 reduced the oncogenic phenotypes of OECM-1 cells. Injection of lentivirus carrying shRNA vectors against STK15 significantly reduced the growth of SAS xenografts on nude mice. Knockdown of STK15 also induced autophagy and apoptosis of OSCC cells. Our data provide evidence that STK15 is oncogenic for OSCC and that its nuclear expression is a predictor of clinical behaviour. Knockdown of STK15 could be a potential therapeutic option in OSCC and other tumours.

A 16-year-old young man had severe loss of alveolar bone and lost four teeth in the anterior maxilla because of traumatic injury in a traffic accident. To overcome the surgically compromised condition for implant rehabilitation, the deficient ridge was augmented by autogenous bone graft from the mandibular symphysis. The augmented ridge had much improvement in width but less in vertical height. Four implants were placed to gain initial osseointegration. Segmental osteotomy was performed to occlusally reposition the implants and bone for 5-mm in the anterior maxilla. After 2 years of clinical follow-up, the rehabilitation outcome is satisfactory and stable.