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MicroRNAs are short non-coding RNAs that regulate gene expression and are crucial to tumorigenesis. Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. Up-regulation of miR-146 has been identified in OSCC tissues. However, the roles of miR-146 in carcinogenesis are controversial as it is suppressive in many other malignancies. The present study investigated the pathogenic implications of miR-146a in oral carcinogenesis. Microdissected OSCC exhibits higher levels of miR-146a expression than matched adjacent mucosal cells. The plasma miR-146a levels of patients are significantly higher than those of control subjects; these levels decrease drastically after tumor resection. miR-146a levels in tumors and in patients' plasma can be used to classify OSCC and non-disease status (sensitivity: >0.72). Exogenous miR-146a expression is significantly increased in vitro oncogenic phenotypes as well as during xenograft tumorigenesis and OSCC metastasis. The plasma miR-146a levels of these mice parallel the xenograft tumor burdens of the mice. A miR-146a blocker abrogates the growth of xenograft tumors. miR-146a oncogenic activity is associated with down-regulation of IRAK1, TRAF6 and NUMB expression. Furthermore, miR-146a directly targets the 3'UTR of NUMB and a region within the NUMB coding sequence when suppressing NUMB expression. Exogenous NUMB expression attenuates OSCC oncogenicity. Double knockdown of IRAK1 and TRAF6, and of TRAF6 and NUMB, enhance the oncogenic phenotypes of OSCC cells. Oncogenic enhancement modulated by miR-146a expression is attenuated by exogenous IRAK1 or NUMB expression. This study shows that miR-146a expression contributes to oral carcinogenesis by targeting the IRAK1, TRAF6 and NUMB genes.

MicroRNAs are short non-coding RNAs that regulate gene expression by RNA interference. Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. miR-146a has been reported to regulate Toll-like receptors and cytokine signaling, which are both crucial for inflammation and oncogenesis. This study identifies that areca nut extract, TNFα and TGFβ up-regulates miR-146a in OSCC cells. The increased expression of miR-146a enhanced the oncogenicity of OSCC cells. In addition, a G to C polymorphism (rs2910164), which is located in the pre-miR-146a and has been associated with functional alterations in miR-146a, was significantly more prevalent among OSCC patients having more advanced nodal involvement. Our analysis also suggested a higher miR-146a expression in OSCC tissues of patients carrying C polymorphism. The present study concluded a higher prevalence of the pre-mir-146a C-variant was associated with OSCC progression in patients with this disease., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Oral squamous cell carcinoma (OSCC) is an important malignant disease around the world. Aberrant expression of MicroRNAs (miRNAs) has been implicated in carcinogenesis of various cancers. In previous studies, up-regulation of miR-181 was observed when OSCC progressed from leukoplakia, dysplasia to invasive carcinoma. However, the function of miR-181 in oral tumorigenesis remains unclear., Materials and Methods: The expression levels of miR-181 in the tissue and plasma of OSCC patients were measured by quantitative RT-PCR. The correlation between miR-181 level and multiple clinical variables were then checked by Mann-Whitney test and Wilcoxon matched pairs test. To study the functional meaning of up-regulated miR-181, migration assay and invasion assay by transwells and colony forming assay were applied to analyze the tumorigenic phenotypes of OSCC cells with ectopical expression of miR-181., Results: Among different clinical variables, over-expression of miR-181 was correlated with lymph-node metastasis, vascular invasion, and a poor survival. Functional assays revealed ectopically over-expressed miR-181 would enhance cell migration and invasion, but not the ability of anchorage-independent growth of OSCC cells. In addition, the up-regulation of miR-181 could be detected both in tumor tissues and plasma., Conclusion: miR-181 may enhance lymph-node metastasis through regulating migration, which could potentially be exploited as a putative biomarker for patients with OSCC., (© 2011 John Wiley & Sons A/S.)

Backgrounds: The chromosome 3q26 locus is a hotspot region carrying oncogenes that frequently altered in neoplasms. ZASC1 is a zinc finger protein transcription factor localized on 3q26. Our previous study showed the frequent amplification of 3q26, including the ZASC1 gene, in oral squamous cell carcinoma (OSCC). This study investigated the copy number changes of ZASC1 gene from primary to recurrent OSCC and the functions of ZASC1 in OSCC cells., Materials and Methods: A total of 27 OSCC patients with primary and recurrent tumors were examined for ZASC1 and TERC copy number changes using Quantitative PCR analysis. Exogenous expression and knockdown of ZASC1 were carried out to specify the oncogenic potential of ZASC1 in OSCC cells., Results: A ZASC1 copy number that has increased from primary to recurrent tumor counterparts in tissue pairs suggested the importance of ZASC1 in tumor progression. The increase of ZASC1 gene copy number in recurrent tumors was associated with the consumption of betel quid in patients. OSCC cells expressing ZASC1-FLAG fusion protein showed increased proliferation. After the knockdown of endogenous ZASC1 expression using small interference RNA, the growth and colony formation of SAS OSCC cells decreased., Conclusions: The findings support the hypothesis that ZASC1 localized on 3q26 contributes to the recurrence of OSCC., (© 2010 John Wiley & Sons A/S.)

MicroRNAs (miRNAs) play important roles in neoplastic process. miR-24 is localized on chromosome 9q22 and 19p13, regions frequently altered in oral squamous cell carcinoma (OSCC). This study showed that miR-24 was up-regulated in OSCC tissues relative to control samples. In addition, the plasma levels of miR-24 in OSCC patients were significantly higher than in control individuals. miR-24 expression was also higher in OSCC cell lines relative to normal oral keratinocytes. Experiments blocking miR-24 and using exogenous miR-24 expression indicated that miR-24 contributes to the growth of OSCC cells and that miR-24 may target p57. This study suggests that miR-24 is involved in the regulation of OSCC growth and that the miR-24's level in plasma may be validatable as a tumor marker for OSCC patients., ((c) 2010 Elsevier Ltd. All rights reserved.)

MicroRNAs (miRNA) are endogenously expressed noncoding RNAs with important biological and pathological functions that are yet to be fully defined. This study investigated alterations in miRNA expression in head and neck squamous cell carcinoma (HNSCC), the incidence of which is rising throughout the world. Initial screening and subsequent analysis identified a panel of aberrantly expressed miRNAs in HNSCC tissues, with miR-31 among the most markedly upregulated. Ectopic expression of miR-31 increased the oncogenic potential of HNSCC cells under normoxic conditions in cell culture or tumor xenografts. Conversely, blocking miR-31 expression reduced the growth of tumor xenografts. The in silico analysis suggested that miR-31 may target the 3' untranslated region (UTR) of factor-inhibiting hypoxia-inducible factor (FIH), a hypoxia-inducible factor (HIF) regulatory factor that inhibits the ability of HIF to act as a transcriptional regulator under normoxic conditions. In support of this likelihood, miR-31 expression repressed FIH expression and mutations within the predictive miR-31 target site in the FIH 3' UTR abrogated FIH repression. Furthermore, miR-31 expression increased HIF transactivation activity. We found that FIH suppressed oncogenic phenotypes under normoxic conditions and that this activity was abrogated by functional mutations. Lastly, increased miR-31 expression was correlated with decreased levels of FIH in tumor tissues. Our findings suggest that miR-31 contributes to the development of HNSCC by impeding FIH to activate HIF under normoxic conditions.

MicroRNAs (miRNAs) are non-coding RNAs that play roles in gene silencing and may be involved in tumorigenesis. miR-211 was mapped to chromosome 15q13, a locus frequently altered in cancers. The role of miR-211 in carcinogenesis has not been clearly defined, however. This study investigated the pathogenetic implications of miR-211 in oral carcinogenesis. An association was found between higher miR-211 expression and the most advanced nodal metastasis, vascular invasion, and poor prognosis of oral carcinoma. The function of enforced miR-211 expression in oral carcinoma cells was confirmed by the repression of LacZ in a reporter plasmid via miR-211 targeting. Enforced miR-211 expression significantly increased the proliferation, migration, and anchorage-independent colony formation of oral carcinoma cells, while it enhanced the tumorigenicity of only SAS high-grade oral carcinoma cells, but not OECM-1 non-tumorigenic cells. The findings suggest that high miR-211 expression may be associated with the progression of oral carcinoma and poor patient outcomes.

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., (Copyright (c) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Many phenolic acid phenethyl esters possess diverse biological effects including anti-cancer activity. A series of 14 derivatives were synthesized for the evaluation of their cytotoxic effect on oral cancer cells. These derivatives were tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric and trypan blue dye exclusion assay on the growth of oral squamous cell carcinoma (SAS), oral epidermoid carcinoma-Meng 1 (OEC-M1), and normal human oral fibroblast (NHOF) cells, respectively. Caffeic acid phenethyl esters, 3a (CAPE), and 3b, 3c, and 3d showed cytotoxic effects on the SAS and OEC-M1 cell lines, but not the NHOF cell line at a 5-100 microM dose range. Flow cytometric analysis showed that 3c caused OEC-M1 cell arrest at G2/M phase. Such differential effects on representative cancer and normal cells suggested these compounds might be useful in oral cancer chemotherapy.