Prognostic Factor For Oral Squamous Cell Carcinoma Patients Research Articles

Increased V-ATPase activity can lead to chemo-resistance in oral squamous cell carcinoma via autophagy induction: new insights.

Oral squamous cell carcinoma (OSCC) is a cancer type with a high rate of recurrence and a poor prognosis. Tumor chemo-resistance remains an issue for OSCC patients despite the availability of multimodal therapy options, which causes an increase in tumor invasiveness. Vacuolar ATPase (V-ATPase), appears to be one of the most significant molecules implicated in MDR in tumors like OSCC. It is primarily responsible for controlling the acidity in the solid tumors' microenvironment, which interferes with the absorption of chemotherapeutic medications. However, the exact cellular and molecular mechanisms V-ATPase plays in OSCC chemo-resistance have not been understood. Uncovering these mechanisms can contribute to combating OSCC chemo-resistance and poor prognosis. Hence, in this review, we suggest that one of these underlying mechanisms is autophagy induced by V-ATPase which can potentially contribute to OSCC chemo-resistance. Finally, specialized autophagy and V-ATPase inhibitors may be beneficial as an approach to reduce drug resistance to anticancer therapies in addition to serving as coadjuvants in antitumor treatments. Also, V-ATPase could be a prognostic factor for OSCC patients. However, in the future, more investigations are required to demonstrate these suggestions and hypotheses.

A novel pyroptosis-related signature predicts prognosis and indicates immunotherapy in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) has been recognized as a frequently occurring oral malignant tumor. Pyroptosis plays an extremely important role in the occurrence and development of cancer, but the role of pyroptosis in OSCC remains unclear. OSCC-related data were obtained from the TCGA and GEO databases. A PSscore risk model was constructed through LASSO regression analysis. The GEO database was utilized as the validation set of the model. The "ESTIMATE" and "CIBERSORT" algorithms were utilized to additionally evaluate the relationship between the immune cell score and PSscore. TIDE and IPS algorithms were used to assess patient response to immunotherapy. In addition, Western blot analysis and MTT assay was used to further validate key genes. Comprehensive bioinformatics analysis showed that a low-PSscore had a significant survival advantage, richer immune cell infiltration, more active immune-related pathways, higher TME scores, and lower tumor purity. The results of TIDE and IPS analysis indicated that the high-PSscore group had higher immune escape potential and was less sensitive to immunotherapy. In contrast, the low-PSscore group patients might be more sensitive to PD1 and CTLA4 + PD1 immunotherapy. Univariate and multivariate COX results indicated that PSscore was an independent prognostic factor in OSCC patients. Another important finding is that BAK1 is a potential target of OSCC and is related to the Nod-like receptor signaling pathway. Knockdown of BAK1 can significantly reduce the proliferation of OSCC cells. The PSscore model could be utilized as a powerful prognostic indicator and can help in the development of new immunotherapies.

Identification of novel prognostic indicators for oral squamous cell carcinoma based on proteomics and metabolomics

BackgroundThe low 5-year survival rate of oral squamous cell carcinoma (OSCC) suggests that new prognostic indicators need to be identified to aid the clinical management of patients. MethodsSaliva samples from OSCC patients and healthy controls were collected for proteomic and metabolomic sequencing. Gene expressed profiling was downloaded from TCGA and GEO databases. After the differential analysis, proteins with a significant impact on the prognosis of OSCC patients were screened. Correlation analysis was performed with metabolites and core proteins were identified. Cox regression analysis was utilized to stratify OSCC samples based on core proteins. The prognostic predictive ability of the core protein was then evaluated. Differences in infiltration of immune cells between the different strata were identified. ResultsThere were 678 differentially expressed proteins (DEPs), 94 intersected DEPs among them by intersecting with differentially expressed genes in TCGA and GSE30784 dataset. Seven core proteins were identified that significantly affected OSCC patient survival and strongly correlated with differential metabolites (R2 > 0.8). The samples were divided into high- and low-risk groups according to median risk score. The risk score and core proteins were well prognostic factor in OSCC patients. Genes in high-risk group were enriched in Notch signaling pathway, epithelial mesenchymal transition (EMT), and angiogenesis. Core proteins were strongly associated with the immune status of OSCC patients. ConclusionsThe results established a 7-protein signatures with the hope of early detection and the capacity for risk assessment of OSCC patient prognosis. Further providing more potential targets for the treatment of OSCC.

Prognostic role of an inflammation scoring system in radical resection of oral squamous cell carcinoma.

BackgroundInflammatory markers can influence the postoperative prognosis and outcome of malignant tumors. However, the role of inflammatory factors in oral squamous cell carcinoma (OSCC) are still debatable. The primary objective of this investigation was to detect the preoperative blood fibrinogen and neutrophil–lymphocyte ratio (NLR) in OSCC patients and to determine the predictive validity of F-NLR (combined fibrinogen and NLR score).MethodsA total of 365 patients with oral cancer after surgery were separated into three classes: F-NLR of 2, with hyperfibrinogenemia (> 250 mg/dL) and high NLR (> 3.2); F-NLR of 1, with only one higher index; and F-NLR of 0, with no higher indices. Univariate and multivariate analyses were used to identify risk factors for the demographic and clinical characteristics of patients in the three F-NLR groups. Kaplan–Meier survival analysis was used to assess the prognosis.ResultsPreoperative F-NLR showed a relatively better predictive role in oral cancer prognosis than fibrinogen and NLR alone. Multivariate analysis revealed that F-NLR has the potential to be an independent predictor for OSCC cancer-specific survival (P < 0.001). Patients with high scores had a relatively poorer prognosis than those with low scores (P < 0.001).ConclusionsOur findings indicate that blood F-NLR may serve as an independent prognostic factor in OSCC patients.

A preoperative prognostic nutritional index is a prognostic indicator in oral squamous cell carcinoma patients undergoing radical surgery

The purpose of this study was to investigate the prognostic value of prognostic nutritional index (PNI) in oral squamous cell carcinoma (OSCC) patients and to undertake a comparative evaluation of the prognostic value of comparing PNI, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in terms of prognostic utility. A retrospective study was conducted involving 203 consecutive patients with OSCC who were treated with radical surgery with curative intent. The PNI and systemic inflammatory response were developed, and their prognostic utility was evaluated. Kaplan–Meier curve analysis and log-rank testing showed that PNI (P< 0.001), NLR (P=0.011), PLR (P=0.013), and LMR (P=0.014) were significantly associated with overall survival. Multivariate analysis identified PNI as an independent prognostic factor for OSCC patients (P=0.029). In time-dependent receiver operating characteristic curve analysis, PNI was continuously superior to that of NLR, PLR, and LMR. In conclusion, this study suggested that PNI offered an independent prognostic biomarker in OSCC patients undergoing radical surgery. However, this study was small and retrospective, thus further investigations are needed to clarify the utility of PNI for tailor-made treatments in clinical settings.

Dysregulation of FOXD2-AS1 promotes cell proliferation and migration and predicts poor prognosis in oral squamous cell carcinoma: a study based on TCGA data.

FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) plays an important role in the pathogenesis of some cancers. However, its functional role in oral squamous cell carcinoma (OSCC) remains largely unknown. In this study, we conducted expressional and functional analyses of FOXD2-AS1 using data from the Cancer Genome Atlas (TCGA) and in vitro OSCC assays. FOXD2-AS1 dysregulation was remarkably associated with radiation therapy, anatomic location, high histologic grade, and lymphovascular invasion (P < 0.05). A nomogram based on FOXD2-AS1 expression was constructed for use as a diagnostic indicator for OSCC patients, and multivariate cox regression analysis showed that FOXD2-AS1 expression was an independent prognostic factor for OSCC patients. KEGG, gene set enrichment analysis, and immune infiltration evaluations indicated that FOXD2-AS1 was involved in tumor progression via epithelial-to-mesenchymal transition and cell cycle regulation and was negatively associated with mast cell, DCs, iDCs, and B cells. FOXD2-AS1 silencing suppressed the proliferation and migration of Cal27 cells. Our findings showed that an aberrantly high FOXD2-AS1 expression predicts poor prognosis in OSCC; FOXD2-AS1 may act as an oncogenic protein by regulating cell proliferation and migration and may suppress adaptive immunity by modulating the number and function of antigen-presenting cells.

Prognostic value of tertiary lymphoid structure and tumour infiltrating lymphocytes in oral squamous cell carcinoma

Tertiary lymphoid structures (TLS) are ectopic lymphoid structures in cancers that are largely associated with favourable prognosis. However, the prognostic value of TLSs in oral squamous cell carcinoma (OSCC) is largely unknown, and the association between tumour infiltrating lymphocytes (TILs) and TLSs has been rarely explored in OSCC. In this study, associated markers of TLS, including peripheral node address (PNAd) in high endothelial venules, CD20 in B cells and CD3 in T cells, were examined in 168 OSCC patients, and survival analysis was performed between TLS-positive and TLS-negative cohorts. We detected the presence of TILs by staining CD8+ cytotoxic T cells and CD57+ NK cells as well. TLSs appeared as highly organized structures in 45 (26.8%) cases. TLS-positive patients had a better 5-year overall survival (OS) rate (88.9% vs. 56.1%, P < 0.001) and relapse-free survival (RFS) rate (88.9% vs. 63.4%, P = 0.002). Moreover, the presence of TLS was an independent prognostic factor for both the 5-year OS rate (hazard ratio [HR] = 3.784; 95% confidence interval [CI], 1.498–9.562) and RFS rate (HR = 3.296; 95% CI, 1.279–8.490) in multivariate analysis. Furthermore, a higher density of CD8+ T cells and CD57+ NK cells was found in TLS-positive sections than in TLS-negative counterparts (P < 0.001), and their combination provided a higher predictive accuracy (AUC = 0.730; 95% CI, 0.654–0.805). In conclusion, our results suggest that TLS is an independent positive prognostic factor for OSCC patients. These findings provide a theoretical basis for the future diagnostic and therapeutic value of TLSs in OSCC treatment.

Circular RNA circMDM2 accelerates the glycolysis of oral squamous cell carcinoma by targeting miR-532-3p/HK2.

Circular RNAs (circRNAs) function as an essential regulator in the progression of oral squamous cell carcinoma (OSCC). However, the potential roles and mechanism of circRNAs in OSCC are still elusive. Here, this research investigates the roles and molecular mechanism of novel circRNA (circMDM2) in OSCC progression. Clinically, circMDM2 was overexpressed in OSCC tissue and cells, and the overexpression served as a poor prognostic factor for OSCC patients. Functionally, cellular experiments confirmed that circMDM2 accelerated OSCC cell proliferation and glycolysis in vitro and circMDM2 knockdown repressed the tumour growth in vivo. Mechanistically, circMDM2 sponged miR‐532‐3p to promote the hexokinase 2 (HK2), forming the circMDM2/miR‐532‐3p/HK2 axis. In conclusion, these findings demonstrated that circMDM2/miR‐532‐3p/HK2 axis promotes the proliferation and glycolysis of OSCC, rendering a potential diagnostic biomarker and prospective therapeutic target for OSCC.

Long non-coding RNA BANCR promotes proliferation and migration in oral squamous cell carcinoma via MAPK signaling pathway.

Long non-coding RNAs (lncRNAs) have been shown to be aberrantly expressed in oral squamous cell carcinoma (OSCC), but the biological role and function of BRAF-activated long non-coding RNA (BANCR) in OSCC remain poorly understood. In this study, we found that the expression of BANCR was upregulated in OSCC tissues and cell lines compared to the negative control. The decreased expression of BANCR in vitro markedly inhibited OSCC cell proliferation, migration, and invasion while the opposite was observed for the overexpression of BANCR. The results also showed that the expression of MAPK signaling-related proteins (p-erk, p-akt, and p-p-38) was positively correlated with that of BANCR. Thus, BANCR may play an important role in the tumorigenesis of OSCC, as well as cell proliferation, migration, and invasion of OSCC, and it may be a potential therapeutic target and prognostic factor in OSCC patients.

KI67 IS AN INDEPENDENT PROGNOSTIC MARKER FOR RECURRENCE AND RELAPSE IN ORAL SQUAMOUS CELL CARCINOMA PATIENTS

Objectives Ki67 expression was associated with the prognosis of several tumors and played a key role in the choice of medical treatments. However, the diagnostic value of Ki67 in oral squamous cell carcinoma (OSCC) has not been fully-evaluated. In this study, we aimed to elucidate the prognosis value of Ki67 in large number of OSCC patients. Findings Ki67 expression was detected by immune-histochemical staining methods in 298 OSCC samples and 98 none-tumor oral mucosa samples (62 dysplasia mucosa and 26 normal mucosa), which were acquired from Nanjing Stomatological Hospital, Medical School of Nanjing University. Expression of Ki67 was assessed independently by two professional pathologists. Expression of Ki67 in normal mucosa, mucosa with dysplasia and OSCC tissue was compared. Correlations between Ki67 expression and clinicopathological parameters were analyzed by Chi-square test. Kaplan-Meier survival curves and cox progression analysis were used to assess the diagnostic value of Ki67 for OSCC. We found that Ki67 expression was higher in OSCC tissues than in non-tumor tissues, and it increases with the progression of dysplasia in oral mucosa tissues. In addition, high Ki67 expression in OSCC patients was associated with poorer tumor differentiation (P=0.001), more lymph node metastasis (P=0.006), and inferior worst pattern of invasion type (WPOI) (P Conclusions Ki67 overexpression is associated with the progression of OSCC and can serve as an independent prognostic factor for OSCC patients

Investigation of the Prognostic Role of Carbonic Anhydrase 9 (CAIX) of the Cellular mRNA/Protein Level or Soluble CAIX Protein in Patients with Oral Squamous Cell Carcinoma.

Carbonic anhydrase 9 (CAIX) is an important protein that stabilizes the extracellular pH value and is transcriptionally regulated by hypoxia-inducible factor 1 (HIF1), but more stable than HIF1α. Here we show a comparative study that examines the prognostic value of CA9 mRNA, CAIX protein of tumor cells and secreted CAIX protein for oral squamous cell carcinoma (OSCC) patients. Tumor samples from 72 OSCC patients and 24 samples of normal tissue were analyzed for CA9 mRNA levels. A total of 158 OSCC samples were stained for CAIX by immunohistochemistry and 89 blood serum samples were analyzed by ELISA for soluble CAIX protein content. Survival analyses were performed by Kaplan–Meier and Cox’s regression analysis to estimate the prognostic effect of CA9/CAIX in OSCC patients. The CA9 mRNA and CAIX protein levels of tumor cells correlated with each other, but not with those of the secreted CAIX protein level of the blood of patients. ROC curves showed a significant (p < 0.001) higher mRNA-level of CA9 in OSCC samples than in adjacent normal tissue. Cox’s regression analysis revealed an increased risk (i) of death for patients with a high CA9 mRNA level (RR = 2.2; p = 0.02), (ii) of locoregional recurrence (RR = 3.2; p = 0.036) at higher CA9 mRNA levels and (iii) of death at high CAIX protein level in their tumors (RR = 1.7; p = 0.066) and especially for patients with advanced T4-tumors (RR = 2.0; p = 0.04). However, the secreted CAIX protein level was only as a trend associated with prognosis in OSCC (RR = 2.2; p = 0.066). CA9/CAIX is an independent prognostic factor for OSCC patients and therefore a potential therapeutic target.

Higher Ki67 expression in fibroblast like cells at invasive front indicates better clinical outcomes in oral squamous cell carcinoma patients.

Background: Ki67 has been a key role for the treatment options and prognosis evaluation in some kinds of tumors; however, the spatial expression of Ki67 in oral squamous cell carcinoma (OSCC) has not been fully-evaluated. Therefore, in the present study, we aimed to elucidate the prognosis value of Ki67 spatial expression including in different cell types and at different compartments of tumor in OSCC patients. Methods: Immunohistochemical expression of Ki67 in tumor cells (TCs) and fibroblast like cells (FLCs) at center of tumor (CT) and invasive front (IF) was evaluated in 109 OSCC patients. Then correlations of Ki67 expressions with clinicopathological parameters were analyzed by Chi-square test, and survival curves were evaluated by Kaplan–Meier methods. Furthermore, univariate and multivariate analysis were performed to assess the diagnostic values of Ki67 expression by the Cox regression model. Results: Ki67 expression in TCs was much higher than in FLCs both at CT and IF compartments, but Ki67 expression in TCs was simultaneously higher at CT than that at IF (P=0.0004), which was converse to Ki67 expression in FLCs (P<0.0001). Additionally, high Ki67 expression in FLCs at IF was significantly associated with poor tumor differentiation (P=0.003), worse depth of invasion (DOI, P=0.027) and worst pattern of invasion (WPOI, P=0.041), but Ki67 expression in TCs had no correlation with clinical parameters no matter at CT or IF. Moreover, patients with higher Ki67 expression in TCs at CT had significantly increased risk for OS (overall survival; HR:1.935, 95% CI: 1.181–4.823, P=0.0395) and DFS (disease-free survival; HR: 2.974, 95% CI:1.189–5.023, P=0.046). On contrary, higher Ki67 expression in FLCs at IF was correlated with better OS (HR: 0.15, 95% CI: 0.018–0.846, P=0.0396) and DFS (HR: 0.15, 95% CI: 0.018–0.947, P=0.0445). Whereas, Ki67 expression both at TCs in IF and at FLCs in CT had no significant prognostic value for OS and DFS. Furthermore, Cox multivariate analysis revealed that Ki67 expression in FLCs at IF could not be an independent prognostic factor for OSCC patients. Conclusion: These results show that higher Ki67 expression in FLCs at IF indicated better clinical outcomes for OSCC patients.

Ki-67 is an independent prognostic marker for the recurrence and relapse of oral squamous cell carcinoma.

As a nuclear and nucleolar protein, proliferation marker protein Ki-67 (Ki-67) serves a vital role in tumorigenesis due to its positive correlation with tumor proliferation. High expression of Ki-67 in the cell cycle from the G1 to M phase makes it a potential biomarker for certain tumors and useful for selecting medical treatment. However, the diagnostic value of Ki-67 in oral squamous cell carcinoma (OSCC) has not been fully evaluated. In the present study, the objective was the elucidation of the prognostic value of Ki-67 in a large number of OSCC patients. Ki-67 expression was detected by immunohistochemical staining methods in 298 OSCC specimens and 98 tumor-free oral mucosa specimens (62 dysplasia mucosa and 36 normal mucosa), acquired from Nanjing Stomatological Hospital, Medical School of Nanjing University (Nanjing, China). Expression of Ki-67 in normal tissues, dysplasia tissues and OSCC tissues was compared. Associations between Ki-67 expression and clinicopathological parameters were analyzed by χ2 test. Kaplan-Meier survival curves and Cox progression analysis were used to assess the diagnostic value of Ki-67 for OSCC. The results showed that Ki-67 expression was higher in OSCC tissues than in tumor-free tissues and that it increased with the progression of dysplasia in oral mucosa tissues. In addition, patients with high Ki-67 expression had a worse clinical outcome, including poor tumor differentiation (P=0.001), increased positive lymph node metastasis (P=0.006) and increased worst pattern of invasion type (P<0.0001). Kaplan-Meier survival analysis demonstrated that higher Ki-67 expression was associated with poorer overall survival (OS) (P=0.035), recurrence-free survival (RFS) (P=0.017), metastasis-free survival (MFS) (P=0.032) and disease-free survival (DFS) (P=0.018) times. Additional multivariate analysis demonstrated that Ki-67 expression was negatively associated with OS, DFS, RFS and MFS. In conclusion, Ki-67 overexpression is associated with the progression of OSCC and serves as an independent prognostic factor for OSCC patients.

Prognostic value of histone H3 serine 10 phosphorylation and histone H4 lysine 12 acetylation in oral squamous cell carcinoma.

Studies on epigenetics in oral squamous cell carcinoma (OSCC) are rare. Histone modifications comprise epigenetic mechanisms that perform a key role in gene transcription and may regulate tumour development. Thus, the aim of this study was to determine whether two post-translational histone modifications, i.e. phosphorylation of serine 10 in histone H3 and acetylation of lysine 12 in histone H4, have prognostic value for OSCC patients. Paraffin-embedded tissue samples of 90 patients diagnosed with OSCC were obtained and subjected to immunohistochemical staining with antibodies against histone H3 with phosphorylation of serine 10 (H3S10ph) and histone H4 with acetylation of lysine 12 (H4K12ac). The associations of H3S10ph and H4K12ac expression levels with clinicopathological factors were determined. Five-year survival analysis and univariate and multivariate analyses were also performed. Both H3S10ph and H4K12ac were expressed in the nuclei of tumour cells. A low median of H3S10ph expression was significantly associated with cervical lymph node metastasis. Tumours with high H4K12ac expression were significantly associated with gender, alcohol consumption, and cervical lymph node metastasis. H4K12ac was also shown to have independent prognostic value in the multivariate analysis. Tumours with high H3S10ph expression, size >40 mm, an advanced stage and the presence of cervical lymph node metastases were associated with a better 5-year survival rate. Tumours with low H4K12ac expression, size >40 mm, an advanced stage and cervical lymph node metastasis were associated with a better 5-year survival rate. These findings suggest that H3S10ph, and mainly H4K12ac, may play a role in OSCC progression and the occurrence of cervical lymph node metastasis. Also, the expression level of H4K12ac could be an independent prognostic factor for OSCC patients.

Sonic Hedgehog Signalling Activation Contributes to ALCAM Over-Expression and Poor Clinical Outcome in Patients with Oral Squamous Cell Carcinoma.

To investigate the Sonic Hedgehog (SHH) signalling molecules and activated leukocyte cell adhesion molecule (ALCAM) expression in the mechanisms regulating invasion and metastasis in oral squamous cell carcinoma (OSCC). The expressions of SHH signalling molecules Gli family zinc finger 1/2 (Gli1/Gli2), as well as ALCAM expression, was analysed in 101 OSCC patients by immunohistochemistry. The potential relationship between Gli1/Gli2 and ALCAM in regard to invasion and metastasis were studied by western blot, invasion and wound-healing assays. Gli1, Gli2 and ALCAM were expressed in 54.5%, 49.5% and 47.5% of the 101 OSCC specimens, respectively. High expression of ALCAM was associated with shorter survival in the patient population (P = 0.018), which was independent of other clinical parameters. Notably, when both ALCAM expression and positive nodal status were considered, an enhanced prediction of clinical outcomes was achieved (P = 0.001). In OSCC cell lines, down-regulation of ALCAM resulted in reduced cell invasion and metastasis. Importantly, SHH activation increased the half-life of ALCAM leading to ALCAM accumulation and increased cell invasion and migration. ALCAM over-expression in OSCC is an independent prognostic factor for OSCC patients. Its over-expression may be the result of the activation of the SHH signalling pathway and contributes to OSCC progression.

Tumor associated tissue eosinophilia: a case report with review

&lt;p class="abstract"&gt;&lt;span lang="EN-IN"&gt;Cancer is one of the most deadly diseases. Even today a lot of research is going on to understand the various aspects of this neoplasm in order to improve the treatment modalities and thus the life of the affected. The role of tumor associated tissue eosinophilia (TATE) has gained much impetus as it is believed to play important role in the biological behavior of the tumor. There are contradictory reports with respect to malignancy and hence its functional role remains ambiguous. We report a case of oral squamous cell carcinoma (OSCC) with TATE and review of literature of the same. A 58 year old female patient presented with a shallow ulcer on the palate. On clinical examination, left submandibular lymph nodes were enlarged and tender on palpation with slightly raised surface temperature. Fine needle aspiration cytology from submandibular lymph nodes was suggestive of squamous cell carcinoma. Incisional biopsy from ulcer confirmed the diagnosis of moderately differentiated squamous cell carcinoma, with the striking feature of tissue eosinophilia. Haematological investigations revealed differential &amp;amp; absolute eosinophil count which was not significant. The review of literature revealed contradictory findings with respect to TATE as a prognostic factor in OSCC patients. It has been found to have a favourable, a poorer or even no influence on patient’s outcome, thus remaining a matter of controversy.&lt;/span&gt;&lt;/p&gt;

Calreticulin is a novel independent prognostic factor for oral squamous cell carcinoma.

We focused on the expression of Calreticulin (CALR) in oral squamous cell carcinoma (OSCC) on the basis of proteomic differential display analysis data. We used QR-32 cells in this study which is a regressive murine fibrosarcoma cell clone; and QRsP-11, a progressive malignant tumor cell clone originated from QR-32. CALR is an endoplasmic reticulum luminal Ca2+-binding chaperone protein, which is thought to affect the tumor behavior of various malignancies. This study was aimed to determine the usefulness of CALR as a prognostic factor in patients with OSCC. We investigated the expression of CALR in tissue samples taken from 111 OSCC patients by immunohistochemistry, and we also analyzed the relationship between CALR expression and patients' clinicopathological characteristics as well as patient survival. Positive immunohistchemical staining of CALR was observed in the cancer cell cytoplasm. Among 111 patients, high expression of CALR was observed in 44 patients (39.6%), whereas low expression was observed in 67 patients (60.4%). Significant association was found between CALR expression and T classification (P=0.0027), N classification (P=0.0219), stage (P=0.0013), and patient outcome (P=0.0014). Log-rank test showed that, there is a significant difference (P<0.0001) in 5-year survival rates between patients showing CALR high-expression (59.1%) and CALR low-expression (86.6%). According to our Multivariate analysis, reduced term survival of patients was correlated to high levels of CALR expression (P<0.0001). Our findings suggest that elevated expression of CALR might play an important role in tumor progression in OSCC, and could be considered as a useful prognostic factor in OSCC patients.

Combined Analysis of Vascular Endothelial Growth Factor Expression with Cyclooxygenase-2 and Mast Cell Density in Oral Squamous Cell Carcinoma

Background: Overexpression of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) and increasing mast cell density (MCD) in premalignant and malignant oral lesions have been documented. However, their correlation with clinicopathologic parameters and survival rate in oral squamous cell carcinoma (OSCC) is not completely clear. This study aimed to assess these subjects. Methods: VEGF, COX-2, and mast cell tryptase expression were examined immunohistochemically in 57 cases of OSCC. The relationships between the markers' expression and clinicopathologic data were assessed using bivariate and multivariate analysis. Results: Spearman's rank correlation coefficient showed a significant correlation between VEGF and COX-2 expression (r = 0.462, p < 0.001), as well as between VEGF expression and MCD (r = 0.306, p < 0.001). Multivariate analysis showed no significant correlation between the markers' immunoexpression and overall survival (OS), but a significant correlation between mode of invasion and OS [hazard ratio 0.362 (95% CI: 0.138- 0.974); p = 0.038] was observed. An association between MCD and gender (p = 0.042) was also found, as MCD was higher in males. Conclusion: The significant correlation of VEGF expression with COX-2 expression and MCD may represent the roles of COX-2 and MCD in tumor angiogenesis by modulating VEGF production. However, VEGF, COX-2, and MCD are not useful indicators to predict prognosis in OSCC. Nevertheless, the mode of invasion can be considered as an independent prognostic factor in OSCC patients.

Plasma miR-187* is a potential biomarker for oral carcinoma.

Oral squamous cell carcinoma (OSCC) is prevalent worldwide, and survival in OSCC has not improved significantly in the past decades. MicroRNAs (miRNAs) have an important regulatory role in oral carcinogenesis. This study investigated the functional and clinical implications of miR-187* in OSCC pathogenesis. Expression of miR-187* in OSCC tissues and patient plasma was assayed using quantitative RT-PCR. The diagnostic power was specified using receiver operator curve analysis. The phenotypic influence of miR-187* in OSCC cells was delineated using exogenous expression. miR-187* was upregulated in OSCC tissue relative to control mucosa. Overexpression of miR-187* enhanced the oncogenic phenotype of OSCC cells, including cell migration and anchorage-independent colony formation. Plasma miR-187* levels could be used to distinguish patients from controls with a separating power of 0.73. Patients showing a reduction in plasma miR-187* after tumor resection had a better prognosis. miR-187* plays oncogenic roles in oral carcinogenesis. Plasma miR-187* could be validated as a marker of OSCC for diagnostic uses. This research implied that plasma miR-187* was a diagnostic marker for patients with OSCC, and plasma miR-187* level could be a prognostic factor for OSCC patients who received ablation surgery.

Skp2 Regulates the Expression of MMP-2 and MMP-9, and Enhances the Invasion Potential of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor of the head and neck regions and accounts for more than 90% of cancers in the oral cavity. S-phase kinase-associated protein-2 (Skp2) is a member of the F-box protein family and the substrate recognition subunit of the Skp1-Cullin-F box protein E3 ubiquitin ligase complex. Skp2 is oncogenic and overexpressed in human cancers. The aims of the present study were to determine the clinicopathological significance of Skp2 in OSCC and clarify its function in OSCC cell lines in vitro. Multiple methods including immunohistochemical staining, RT-PCR, western blotting, migration and invasion assays, and siRNA transfection were employed in order to investigate the clinicopathological significance and molecular function of Skp2 in OSCC. The overexpression of Skp2 was more frequent in OSCC than in the normal oral epithelium. It was also more frequently detected in cancers with higher grades according to the T classification, N classification, and pattern of invasion. The high-Skp2 expression group had a significantly poorer prognosis, at 30.1%, than that of the low-expression group, at 63.0%. The downregulation of Skp2 decreased migration and invasion potentials in HSC3 cells. Moreover, the suppression of Skp2 reduced the enzyme activities of MMP-2 and MMP-9 via Sp1. Skp2 may be a prognostic factor in OSCC patients, and may also play crucial roles in the migration and invasion potentials of OSCC cells.