Electro-optic properties of liquid crystal cells with nanowall electrodes.

This work fabricates a nanowall electrode for achieving advanced liquid crystal (LC) devices and improving LC displays. The nanowall electrode consists of indium-tin-oxide (ITO) sheets stacked with nanowalls, and the nanowalls have a height and thickness of 4 µm and 500 nm, respectively. The high aspect ratio (8.0) of the nanowalls sets the nanowall electrode apart from previous electrodes. A flat electrode that comprises only ITO sheets is used to evaluate the nanowall electrode. The LC cell with the nanowall electrode exhibits better electro-optic properties than the LC cell with the flat electrode due to the strong transverse electric field and small subelectrode gap of the nanowall electrode. Especially, the operating voltage (3.7 V) of the nanowall cell is 36% smaller than that (5.8 V) of the flat cell. Therefore, nanowall electrodes have potential in LC lenses, LC antennas, metaverse displays, and digital optics.

Phocaeicola oris sp. nov., an anaerobic bacterium isolated from the saliva of a patient with oral squamous cell carcinoma.

A Gram-stain-negative or -positive, strictly anaerobic, non-spore-forming and pleomorphic bacterium (designated 14-104T) was isolated from the saliva sample of a patient with oral squamous cell carcinoma. It was an acid-tolerant neutralophilic mesophile, growing at between 20 and 40 °C (with optimum growth at 30 °C) and pH between pH 3.0 and 7.0 (with optimum growth at pH 6.0-7.0). It contained anteiso-C15 : 0 and C15 : 0 as the major fatty acids. The genome size of strain 14-104T was 2.98 Mbp, and the G+C content was 39.6 mol%. It shared <87 % 16S rRNA sequence similarity, <71 % orthologous average nucleotide identity, <76 % average amino acid identity and <68 %% of conserved proteins with its closest relative, Phocaeicola abscessus CCUG 55929T. Reconstruction of phylogenetic and phylogenomic trees revealed that strain 14-104T and P. abscessus CCUG 55929T were clustered as a distinct clade without any other terminal node. The phylogenetic and phylogenomic analyses along with physiological and chemotaxonomic data indicated that strain 14-104T represents a novel species in the genus Phocaeicola, for which the name Phocaeicola oris sp. nov. is proposed. The type strain is 14-104T (=BCRC 81305T= NBRC 115041T).

Epigenetic Deregulation of Protein Tyrosine Kinase 6 Promotes Carcinogenesis of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) accounts for over 90% of oral cancers and causes considerable morbidity and mortality. Epigenetic deregulation is a common mechanism underlying carcinogenesis. DNA methylation deregulation is the epigenetic change observed during the transformation of normal cells to precancerous and eventually cancer cells. This study investigated the DNA methylation patterns of PTK6 during the development of OSCC. Bisulfite genomic DNA sequencing was performed to determine the PTK6 methylation level. OSCC animal models were established to examine changes in PTK6 expression in the different stages of OSCC development. The DNA methylation of PTK6 was decreased during the development of OSCC. The mRNA and protein expression of PTK6 was increased in OSCC cell lines compared with human normal oral keratinocytes. In mice, the methylation level of PTK6 decreased after treatment with 4-nitroquinoline 1-oxide and arecoline, and the mRNA and protein expression of PTK6 was increased. PTK6 hypomethylation can be a diagnostic marker of OSCC. Upregulation of PTK6 promoted the proliferation, migration, and invasion of OSCC cells. PTK6 promoted carcinogenesis and metastasis by increasing STAT3 phosphorylation and ZEB1 expression. The epigenetic deregulation of PTK6 can serve as a biomarker for the early detection of OSCC and as a treatment target.

Single-Cell RNA Sequencing Analysis for Oncogenic Mechanisms Underlying Oral Squamous Cell Carcinoma Carcinogenesis with Candida albicans Infection.

Oral squamous cell carcinoma (OSCC) carcinogenesis involves heterogeneous tumor cells, and the tumor microenvironment (TME) is highly complex with many different cell types. Cancer cell-TME interactions are crucial in OSCC progression. Candida albicans (C. albicans)-frequently pre-sent in the oral potentially malignant disorder (OPMD) lesions and OSCC tissues-promotes malignant transformation. The aim of the study is to verify the mechanisms underlying OSCC car-cinogenesis with C. albicans infection and identify the biomarker for the early detection of OSCC and as the treatment target. The single-cell RNA sequencing analysis (scRNA-seq) was performed to explore the cell subtypes in normal oral mucosa, OPMD, and OSCC tissues. The cell composi-tion changes and oncogenic mechanisms underlying OSCC carcinogenesis with C. albicans infec-tion were investigated. Gene Set Variation Analysis (GSVA) was used to survey the mechanisms underlying OSCC carcinogenesis with and without C. albicans infection. The results revealed spe-cific cell clusters contributing to OSCC carcinogenesis with and without C. albicans infection. The major mechanisms involved in OSCC carcinogenesis without C. albicans infection are the IL2/STAT5, TNFα/NFκB, and TGFß signaling pathways, whereas those involved in OSCC carcinogenesis with C. albicans infection are the KRAS signaling pathway and E2F target down-stream genes. Finally, stratifin (SFN) was validated to be a specific biomarker of OSCC with C. albicans infection. Thus, the detailed mechanism underlying OSCC carcinogenesis with C. albicans infection was determined and identified the treatment biomarker with potential precision medicine applications.

Continuously tunable intensity modulators with large switching contrasts using liquid crystal elastomer films that are deposited with terahertz metamaterials.

A liquid crystal elastomer (LCE) film is successfully deposited with a terahertz metamaterial using thermal evaporation via a programmed electronic shutter and high-efficiency cooling system. The transmittance of the metamaterial at its resonance frequency is monotonically increased from 0.0036 to 1.0 as a pump beam bends the LCE film, so the metamaterial has a large switching contrast of 277 at the frequency. The monotonic increase in the resonance transmittance arises from the constant resonance frequency of the metamaterial at the transmittance modulation and depicts that the metamaterial-deposited LCE film can continuously tune the transmitted intensity of a terahertz beam. The metamaterial-deposited LCE film has potential in developing continuously tunable intensity modulators with large switching contrasts for the application of terahertz imaging and terahertz communication. Therefore, the thermal evaporation expands the application of metamaterials and improves their optical properties.

Single-Cell Analysis of Different Stages of Oral Cancer Carcinogenesis in a Mouse Model.

Oral carcinogenesis involves the progression of the normal mucosa into potentially malignant disorders and finally into cancer. Tumors are heterogeneous, with different clusters of cells expressing different genes and exhibiting different behaviors. 4-nitroquinoline 1-oxide (4-NQO) and arecoline were used to induce oral cancer in mice, and the main factors for gene expression influencing carcinogenesis were identified through single-cell RNA sequencing analysis. Male C57BL/6J mice were divided into two groups: a control group (receiving normal drinking water) and treatment group (receiving drinking water containing 4-NQO (200 mg/L) and arecoline (500 mg/L)) to induce the malignant development of oral cancer. Mice were sacrificed at 8, 16, 20, and 29 weeks. Except for mice sacrificed at 8 weeks, all mice were treated for 16 weeks and then either sacrificed or given normal drinking water for the remaining weeks. Tongue lesions were excised, and all cells obtained from mice in the 29- and 16-week treatment groups were clustered into 17 groups by using the Louvain algorithm. Cells in subtypes 7 (stem cells) and 9 (keratinocytes) were analyzed through gene set enrichment analysis. Results indicated that their genes were associated with the MYC_targets_v1 pathway, and this finding was confirmed by the presence of cisplatin-resistant nasopharyngeal carcinoma cell lines. These cell subtype biomarkers can be applied for the detection of patients with precancerous lesions, the identification of high-risk populations, and as a treatment target.

Subsequent thyroid disorders associated with treatment strategy in head and neck cancer patients: a nationwide cohort study.

BACKGROUND: We investigated the risk of thyroid disorders, namely hypothyroidism, thyrotoxicosis and thyroiditis, in head and neck cancer patients undergoing multimodal treatment. METHODS: A cohort study design using Taiwan's National Health Insurance Research Database was used to assess head and neck cancer patients over 20 years old. The cohort was divided into one group who underwent primary tumor excision only (PTE) and another with additional neck dissection (PTE + ND). The tumor sites were stratified to estimate the tumor-site-specific risk of thyroid disorders. The effect of subsequent resurgery, radiotherapy (RT), chemotherapy (CT), and concomitant (CCRT) or sequential chemoradiation therapy (sequential CT+ RT) on the risk of thyroid disorders was explored. RESULTS: For 1999-2012, 7460 patients who underwent PTE + ND and 3730 who underwent PTE were enrolled and followed-up until the end of 2013. There were 122 and 50 patients in the two groups, respectively, who developed thyroid disorders, with no statistical difference between the groups. Patients with hypopharyngeal, oropharyngeal, or laryngeal cancer in the PTE + ND group had a higher risk of thyroid disorders (adjusted HR: 1.50, 95% CI: 0.67-3.38) than those in the PTE group when adjusted for covariates and mortality. Patients who underwent subsequent RT (adjusted HR: 3.64, 95% CI: 1.05-2.77) and CCRT (adjusted HR: 1.70, 95% CI: 1.05-2.77) after PTE + ND had a significantly higher risk of thyroid disorders. CONCLUSION: RT results in a major risk of subsequent thyroid disorders, and ND may exacerbate this effect. Physicians should monitor thyroid function from two years after treatment initiation, especially in patients who undergo ND and subsequent RT.

Development of a Multiplexed Assay for Oral Cancer Candidate Biomarkers Using Peptide Immunoaffinity Enrichment and Targeted Mass Spectrometry.

Oral cancer is one of the most common cancers worldwide, and there are currently no biomarkers approved for aiding its management. Although many potential oral cancer biomarkers have been discovered, very few have been verified in body fluid specimens in parallel to evaluate their clinical utility. The lack of appropriate multiplexed assays for chosen targets represents one of the bottlenecks to achieving this goal. In the present study, we develop a peptide immunoaffinity enrichment-coupled multiple reaction monitoring-mass spectrometry (SISCAPA-MRM) assay for verifying multiple reported oral cancer biomarkers in saliva. We successfully produced 363 clones of mouse anti-peptide monoclonal antibodies (mAbs) against 36 of 49 selected targets, and characterized useful mAbs against 24 targets in terms of their binding affinity for peptide antigens and immuno-capture ability. Comparative analyses revealed that an equilibrium dissociation constant (KD ) cut-off value < 2.82 × 10-9 m could identify most clones with an immuno-capture recovery rate >5%. Using these mAbs, we assembled a 24-plex SISCAPA-MRM assay and optimized assay conditions in a 25-µg saliva matrix background. This multiplexed assay showed reasonable precision (median coefficient of variation, 7.16 to 32.09%), with lower limits of quantitation (LLOQ) of <10, 10-50, and >50 ng/ml for 14, 7 and 3 targets, respectively. When applied to a model saliva sample pooled from oral cancer patients, this assay could detect 19 targets at higher salivary levels than their LLOQs. Finally, we demonstrated the utility of this assay for quantification of multiple targets in individual saliva samples (20 healthy donors and 21 oral cancer patients), showing that levels of six targets were significantly altered in cancer compared with the control group. We propose that this assay could be used in future studies to compare the clinical utility of multiple oral cancer biomarker candidates in a large cohort of saliva samples.

Saliva protein biomarkers to detect oral squamous cell carcinoma in a high-risk population in Taiwan.

Most cases of oral squamous cell carcinoma (OSCC) develop from visible oral potentially malignant disorders (OPMDs). The latter exhibit heterogeneous subtypes with different transformation potentials, complicating the early detection of OSCC during routine visual oral cancer screenings. To develop clinically applicable biomarkers, we collected saliva samples from 96 healthy controls, 103 low-risk OPMDs, 130 high-risk OPMDs, and 131 OSCC subjects. These individuals were enrolled in Taiwan's Oral Cancer Screening Program. We identified 302 protein biomarkers reported in the literature and/or through in-house studies and prioritized 49 proteins for quantification in the saliva samples using multiple reaction monitoring-MS. Twenty-eight proteins were successfully quantified with high confidence. The quantification data from non-OSCC subjects (healthy controls + low-risk OPMDs) and OSCC subjects in the training set were subjected to classification and regression tree analyses, through which we generated a four-protein panel consisting of MMP1, KNG1, ANXA2, and HSPA5. A risk-score scheme was established, and the panel showed high sensitivity (87.5%) and specificity (80.5%) in the test set to distinguish OSCC samples from non-OSCC samples. The risk score >0.4 detected 84% (42/50) of the stage I OSCCs and a significant portion (42%) of the high-risk OPMDs. Moreover, among 88 high-risk OPMD patients with available follow-up results, 18 developed OSCC within 5 y; of them, 77.8% (14/18) had risk scores >0.4. Our four-protein panel may therefore offer a clinically effective tool for detecting OSCC and monitoring high-risk OPMDs through a readily available biofluid.

Autotransplantation of Odontoma-Associated Impacted Teeth-A Treatment Strategy for Satisfying Immediate Esthetic Demands: A Case Report.

Compound odontomas are common odontogenic tumors associated with permanent tooth impaction in the premaxilla. This report describes the case of a 14-year-old girl with an odontoma-associated impaction over the premaxilla that was treated using autotransplantation to satisfy an immediate esthetic demand. At postoperative follow-up conducted in the 14th month, a satisfactory cosmetic appearance with a healthy periodontal status was observed. In addition, the authors discuss the possible complications of autotransplantation and different treatment strategies for odontoma-associated impaction and for correcting bone defects in this case report. Autotransplantation for treating odontoma-associated impaction can be an alternative solution for satisfying an immediate cosmetic demand and providing a favorable outcome.

Temporal relationship between dysthymia and temporomandibular disorder: a population-based matched case-control study in Taiwan.

BACKGROUND: Numerous studies have reported a relationship between depression and temporomandibular disorders (TMD), but the conclusions remain undefined. The aim of this article was to examine the temporal relationship between depression and TMD. METHODS: In this retrospective matched case-control study, we recruited all samples from a randomsample sub-dataset of one million insured individuals for the year 2005 (Longitudinal Health Insurance Database (LHID2005)). All beneficiaries were enrolled in the National Health Insurance (NHI) programme in Taiwan. We used propensity scoring and matched the case and control groups (1:1) by ten confounding factors to detect the effect of different types of depression on TMD. RESULTS: The positive correlative factors of TMD included the total number of times medical advice was sought for an unspecified anomaly of jaw size plus malocclusion (TTSMA-JS, p = 0.045), the total number of times medical advice was sought for an anxiety state (TTSMA-AS, p = 0.000), and the total number of times medical advice was sought for a panic disorder (TTSMA-P, p = 0.009). Dysthymia (synonymous with chronic depression) had an effect on TMD. The odds ratio (OR) of dysthymia for TMD measured by multiple logistic regression was 1.91 (p = 0.008) after adjusting for demographic factors, psychiatric comorbidities, and maxillofacial confounders. CONCLUSIONS: This study demonstrated the established temporal relationship between dysthymia and TMD. The inclusion of a psychiatrist on the TMD management team is appropriate.

Effect of swelling of a photoresist on electromagnetic resonance of terahertz metamaterials.

This work uses isopropyl alcohol (IPA) to develop a photoresist. IPA dissolves the photoresist that is not exposed to UV light, and swells the photoresist that is exposed to UV light. The swelling of the photoresist distorts the split-ring resonators (SRRs). The distorted SRRs have a larger loop length, smaller line width, and smaller split gap than undistorted SRRs. The change in the dimensions of the SRRs is caused by the extension of the SRR arms in their longitudinal directions. The resonance frequency of the distorted SRRs is smaller than that of the undistorted SRRs, and the resonance frequency decreases with the development time. The resonance frequency of the distorted SRRs depends on not only their dimensions, but also the bending of their arms. The distorted SRRs in this work have a frequency tuning range with a maximum width of 0.13 THz. The method that is proposed herein uses IPA to fabricate passively tunable terahertz metamaterials, which exhibit the advantages of high reliability, low cost, and ease of fabrication.

Reducing Trismus After Surgery and Radiotherapy in Oral Cancer Patients: Results of Alternative Operation Versus Traditional Operation.

PURPOSE: In patients with oral cancer, trismus (maximum interincisal opening [MIO] <35 mm) can develop as a result of surgery and radiotherapy. The aim of this study was to provide an alternative operation to both eradicate oral cancer and prevent postsurgical trismus. MATERIALS AND METHODS: In our retrospective cohort study of oral cancer patients who underwent operations during 2010 to 2014, the predictor variable was the type of operation (alternative operation or traditional operation) and the outcome variable was MIO. All of the cases were allocated by 2 periods: the traditional operations were performed from 2010 to 2011, and the alternative operations were performed from 2011 to 2014. All patients received marginal mandibulectomy, anterolateral thigh free flap, and adjuvant radiotherapy or concurrent chemoradiotherapy. In addition to traditional marginal mandibulectomy, the alternative operation included ipsilateral coronoidectomy and myotomy of the temporalis muscle insertion, masseter muscle, and medial pterygoid muscle. MIO was measured at 10 time points. The adjusted variables included demographic data, diagnostic parameters, treatment, and response. RESULTS: Of the 36 male patients with oral cancer, 16 were placed in the alternative operation group (AOG; mean age, 53.5 ± 11.9 years) and 20 were placed in the traditional operation group (TOG; mean age, 50.7 ± 7.1 years). Regarding the outcome indicator of patient MIO, the preoperative MIO in the AOG was on average 7.5 mm shorter than that in the TOG (P < .01), but it was consistently superior to the MIO in the TOG after the operation. Multivariate analysis of variance showed that patients in the AOG were more likely to have postoperative non-trismus. CONCLUSIONS: The alternative operation exhibited superior postoperative MIO values and similar postoperative complication rates. For the prevention of trismus, it is practical to perform the combined operation simultaneously, cutting all ipsilateral jaw closing muscles and the coronoid process and eradicating the tumor.

The Use of Solid-Phase Concentrated Growth Factors for Surgical Defects in the Treatment of Dysplastic Lesions of the Oral Mucosa.

PURPOSE: Use of the skin graft and artificial dermis to reconstruct a defect after the excision of dysplastic lesions of the oral mucosa has been practiced for years. The purpose of this case series was to introduce a novel resolution-that is, an operating procedure using solid-phase concentrated growth factors (SPCGFs) to reconstruct oral mucosa defects-and observe the postoperative results and evaluate its clinical effects. MATERIALS AND METHODS: In this consecutive serial case study of patients with oral dysplastic lesions who underwent operations from April 2015 through July 2015, the primary endpoint of the study was to observe the clinical wound-healing profile at 1 week, 3 weeks, 3 months, and 6 months postoperatively. The secondary endpoint was to observe maximal interincisal opening (MIO) and wound pain preoperatively and at 1 and 3 days, 1 and 3 weeks, and 3 and 6 months postoperatively. The minimum follow-up was 8 months, and the longest was 1 year. RESULTS: All sites had healed with complete epithelialization after 3 weeks postoperatively. All patients had a wound-healing score no higher than 3 at 3 weeks postoperatively. The preoperative MIO was 52 ± 4.64 mm and the 6-month postoperative MIO was 49.2 ± 3.03 mm. No patient reported further pain from 3 weeks postoperatively. No recurrence of the lesion was found at or after the 6-month follow-up period. CONCLUSION: The results of this study show that the use of SPCGFs to reconstruct oral mucosa defects is feasible and practical. The efficacy of SPCGFs needs to be verified by additional studies with higher-level evidence bases in the future.

Continuously tunable and fast-response terahertz metamaterials using in-plane-switching dual-frequency liquid crystal cells.

A metamaterial that is embedded in an in-plane-switching dual-frequency liquid crystal cell is used to develop an electrically controllable terahertz (THz) metamaterial. The resonance peak of the metamaterial can be redshifted and blueshifted as the frequency of an external voltage is switched, and the response times for the redshift and blueshift are 1.044 and 1.376 ms, respectively. A simulation confirms the spectral redshift and blueshift. The variation in peak frequency as a function of applied frequency at the external voltage is presented. Experimental results show that the resonance peak of the metamaterial can be continuously tuned within a frequency range of 15 GHz as the applied frequency is switched between 19 and 22 kHz. Therefore, this metamaterial is a continuously tunable and fast-response THz filter and could be used for THz imaging and THz telecommunications.

The application of data mining techniques to oral cancer prognosis.

This study adopted an integrated procedure that combines the clustering and classification features of data mining technology to determine the differences between the symptoms shown in past cases where patients died from or survived oral cancer. Two data mining tools, namely decision tree and artificial neural network, were used to analyze the historical cases of oral cancer, and their performance was compared with that of logistic regression, the popular statistical analysis tool. Both decision tree and artificial neural network models showed superiority to the traditional statistical model. However, as to clinician, the trees created by the decision tree models are relatively easier to interpret compared to that of the artificial neural network models. Cluster analysis also discovers that those stage 4 patients whose also possess the following four characteristics are having an extremely low survival rate: pN is N2b, level of RLNM is level I-III, AJCC-T is T4, and cells mutate situation (G) is moderate.

STRESS-responsive deacetylase SIRT3 is up-regulated by areca nut extract-induced oxidative stress in human oral keratinocytes.

Areca chewing is an important environmental risk factor for development of oral premalignant lesions and cancer. Epidemiological evidence indicates that areca chewing is tightly linked to oral carcinogenesis. However, the pathogenetic impacts of areca nut extract (ANE) on normal human oral keratinocytes (HOKs) are unclear and possibly involve oxidative stress via redox imbalance. Sirtuin 3 (SIRT3) is a member of the sirtuin family of proteins that play an important role in regulating cellular reactive oxygen species (ROS) production. Recent studies have confirmed that ANE and other areca ingredients can induce ROS. In this study, we examined the role of SIRT3 in the regulation of ANE-induced ROS in HOK cells. We examined HOK cell viability following treatment with various ANE concentrations. ANE-induced cytotoxicity increased in a dose-dependent manner and was approximately 48% at a concentration of 50 µg/ml after 24 h. SIRT3 expression and enzyme activity were up-regulated in HOK cells by ANE-induced oxidative stress. Additionally, we identified that SIRT3 controls the enzymatic activity of mitochondrial proteins, such as forkhead box O3a (Foxo3a) transcription factor and antioxidant-encoding gene superoxide dismutase 2 (SOD2), by deacetylation in HOK cells. Moreover, SIRT3-mediated deacetylation and activation of Foxo3a promotes nuclear localization in vivo. These findings suggest that SIRT3 is an endogenous negative regulator in response to ANE-induced oxidative stress and demonstrate an essential role for redox balance in HOK cells.

Role of SIRT1 in regulation of epithelial-to-mesenchymal transition in oral squamous cell carcinoma metastasis.

BACKGROUND: The epithelial-to-mesenchymal transition (EMT) process results in a loss of cell-cell adhesion, increased cell mobility, and is crucial for enabling the metastasis of cancer cells. Recently, the enzyme SIRT1 has been implicated in a variety of physiological processes; however, its role in regulating oral cancer metastasis and EMT is not fully elucidated. Here, we propose a mechanism by which the enzyme sirtuin1 (SIRT1) regulates the EMT process in oral cancer by deacetylating Smad4 and repressing the effect of TGF-ß signaling on matrix metalloproteinase-7 (MMP7). METHODS: The roles of SIRT1 in tumor cell migration/invasion and metastasis to the lungs were investigated using the Boyden chamber assay and orthotopic injections, respectively. RNA interference was used to knockdown either SIRT1 or Smad4 expression in oral squamous cell carcinoma (OSCC) cell lines. Immunoblotting, zymographic assays, and co-immunoprecipitation were used to examine the effects of SIRT1 overexpression on MMP7 expression and activity, as well as on SIRT1/ Smad4 interaction. RESULTS: We found that compared with normal human oral keratinocytes (HOKs), SIRT1 was underexpressed in OSCC cells, and also in oral cancer tissues obtained from 14 of 21 OSCC patients compared with expression in their matched normal tissues. Overexpression of SIRT1 inhibited migration of OSCC cells in vitro, as well as their metastasis to the lung in vivo. Furthermore, up-regulation of SIRT1 in metastatic OSCCs significantly inhibited the migration and invasion abilities of OSCC cells, while concomitantly increasing the expression of E-cadherin, and decreasing the expressions of mesenchymal markers. We also identified Smad4, a TGF-ß-activated transcription factor, as a direct target protein for SIRT1. Overexpression of SIRT1 in OSCC cells led to decreased levels of acetylated Smad4, and inhibition of TGF-ß-induced signaling. By associating and deacetylating Smad4, SIRT1 enzyme can influence MMP7 expression, MMP enzyme activity, and consequently, cell migration, invasion, and tumor metastasis in OSCCs. CONCLUSIONS: These findings provide a valuable insight into the potential role of the SIRT1 enzyme in regulating cell migration and invasion in oral squamous cell carcinoma. Our findings suggest the SIRT1/Smad4/MMP7 pathway as a target for oral cancer driven by EMT.

Galectin-1 induces vascular permeability through the neuropilin-1/vascular endothelial growth factor receptor-1 complex.

Galectin-1 (Gal-1) is a ß-galactoside-binding lectin that regulates endothelial cell migration, proliferation, and adhesion. However, the effect of Gal-1 on vascular permeability and the underlying mechanisms are unclear. We found that high Gal-1 expression was associated with elevated tumor vascular permeability in specimens of oral squamous cell carcinoma. Using transendothelial passage of FITC-dextran and a Miles assay, we demonstrated that Gal-1 increased vascular permeability extracellularly through its carbohydrate recognition domain. Mechanism dissection revealed that the neuropilin (NRP)-1/vascular endothelial growth factor receptor- (VEGFR)-1 complex was required for Gal-1-regulated vascular permeability. Activation of VEGFR-1 triggered activation of Akt which led to a reduction in vascular endothelial-cadherin at cell-cell junctions and resulted in cytoskeletal rearrangement. Both inhibition of Gal-1 secreted from cancer cells and administration of an anti-Gal-1 antibody in the tumor microenvironment suppressed tumor growth and vascular permeability in xenograft models. In conclusion, our results demonstrate a novel function of Gal-1 of increasing vascular permeability through the NRP-1/VEGFR1 and Akt signaling pathway and indicate that targeting Gal-1 by an anti-Gal-1 antibody is a feasible therapy for vascular hyperpermeability and cancer.

Src-homology 2 domain-containing tyrosine phosphatase 2 promotes oral cancer invasion and metastasis.

BACKGROUND: Tumor invasion and metastasis represent a major unsolved problem in cancer pathogenesis. Recent studies have indicated the involvement of Src-homology 2 domain-containing tyrosine phosphatase 2 (SHP2) in multiple malignancies; however, the role of SHP2 in oral cancer progression has yet to be elucidated. We propose that SHP2 is involved in the progression of oral cancer toward metastasis. METHODS: SHP2 expression was evaluated in paired oral cancer tissues by using immunohistochemical staining and real-time reverse transcription polymerase chain reaction. Isogenic highly invasive oral cancer cell lines from their respective low invasive parental lines were established using a Boyden chamber assay, and changes in the hallmarks of the epithelial-mesenchymal transition (EMT) were assessed to evaluate SHP2 function. SHP2 activity in oral cancer cells was reduced using si-RNA knockdown or enforced expression of a catalytically deficient mutant to analyze migratory and invasive ability in vitro and metastasis toward the lung in mice in vivo. RESULTS: We observed the significant upregulation of SHP2 in oral cancer tissues and cell lines. Following SHP2 knockdown, the oral cancer cells markedly attenuated migratory and invasion ability. We observed similar results in phosphatase-dead SHP2 C459S mutant expressing cells. Enhanced invasiveness was associated with significant upregulation of E-cadherin, vimentin, Snail/Twist1, and matrix metalloproteinase-2 in the highly invasive clones. In addition, we determined that SHP2 activity is required for the downregulation of phosphorylated ERK1/2, which modulates the downstream effectors, Snail and Twist1 at a transcript level. In lung tissue sections of mice, we observed that HSC3 tumors with SHP2 deletion exhibited significantly reduced metastatic capacity, compared with tumors administered control si-RNA. CONCLUSIONS: Our data suggest that SHP2 promotes the invasion and metastasis of oral cancer cells. These results provide a rationale for further investigating the effects of small-molecule SHP2 inhibitors on the progression of oral cancer, and indicate a previously unrecognized SHP2-ERK1/2-Snail/Twist1 pathway that is likely to play a crucial role in oral cancer invasion and metastasis.