Shengwen Liu

Activation of Toll-like receptor-9 promotes cellular migration via up-regulating MMP-2 expression in oral squamous cell carcinoma.

Purpose Activation of Toll like receptors (TLRs) signaling has been implicated in promoting malignant cell invasion and metastatic potential. Previously we demonstrated that increased TLR-9 expression predicted poor survival in oral cancer patients. The objective of this study is to further investigate the roles and potential molecular mechanisms of TLR-9 signaling in human oral cancer cell invasion. Methods Cell migration, invasion and protein expression were detected by wound healing assay, Transwell chambers model and western blot. The secretion and activity levels of metalloproteinases-2/9 were quantified by ELISA and Gelatin zymography. EMSA and ChIP assays were employed to detect the activity of AP-1signal pathway. TLR-9 siRNA transfection was used to regulate the expression and activity of TLR-9 in oral cancer cell line HB cells. Result The results of both wound healing assay and in vitro Transwell assay revealed that activation of TLR-9 induced dose- and time- dependent migration and invasion of HB cells. An increased expression, secretion and activity of MMP-2 were observed upon the treatment of CpG-ODN. The TLR-9 signaling-mediated MMP-2 expression appeared to be a consequence of AP-1 activation, because that their DNA binding activity was enhanced by CpG-ODN treatment. All these influences were efficiently repressed by the knockdown of TLR-9 through siRNA or pretreatment of an AP-1 inhibitor. Conclusion Activation of TLR-9 signaling could promote human oral cancer HB cells invasion with the induction of MMP-2 presentation by attenuating AP-1 binding activity, suggesting a novel anti-metastatic application for TLR-9 targeted therapy in oral cancer in the future.

Cyclin D1 Overexpression Is Associated with Poor Clinicopathological Outcome and Survival in Oral Squamous Cell Carcinoma in Asian Populations: Insights from a Meta-Analysis

Background The clinicopathological significance of cyclin D1 overexpression and prognosis of oral squamous cell carcinoma has not been fully quantified. We performed a comprehensive meta-analysis for evaluation of cyclin D1 overexpression in oral squamous cell carcinoma to determine the strength of this association. Methods Using both medical subheadings and free terms, we searched PubMed, Embase and the Institute for Scientific Information Web of Science for all eligible studies published before Nov. 2013. We retrieved 1674 citations, determining that 15 met the selection criteria. We used the odds ratio (OR) and hazard ratio (HR) as the common measures of association to quantitatively determine the correlation between cyclin D1 overexpression and outcomes of oral cancer. We performed a meta-analysis and heterogeneity, sensitivity, and subgroup analyses to clarify and validate the pooled results. Results The pooled results provided compelling evidence that cyclin D1 overexpression was significantly correlated with increased tumor size (OR = 1.617, 95% confidence interval [CI] = 1.046–2.498, p = 0.031), lymphoid node metastasis (OR = 2.035, 95% CI = 1.572–2.635, p<0.001), tumor differentiation (OR = 1.976, 95% CI = 1.363–2.866, p<0.001), and advancement of clinical stages (OR = 1.516, 95% CI = 1.140–2.015, p = 0.004), and adversely influenced overall survival of OSCC patients (HR = 1.897, 95% CI = 1.577–2.282, p<0.001). The strength of association varied in different oral cavity subsites. Conclusion Our findings indicated that cyclin D1 expression correlates with detrimental clinicopathological outcome and poor prognosis in oral squamous cell carcinoma. Our results may be useful in the management of oral cancer.

Vascularized versus nonvascularized facial nerve grafts using a new rabbit model.

Background: The use of vascularized nerve graft models has been limited because of the complexity of the operation. The authors sought to develop a simple and effective rabbit model for facial nerve repair and evaluated its advantages over conventional nerve grafts. Methods: Rabbits were divided into three groups consisting of six rabbits each. The central auricular nerve and its nutrient vessels were used as a vascularized graft. Rabbits were grafted with a vascularized facial nerve graft (vascularized nerve graft group), with a free nerve graft (free nerve graft group), or with a vascularized nerve graft and a free nerve graft on each side of the face (vascularized nerve graft/free nerve graft group). Four months after surgery, facial performance and electrophysiologic monitoring were evaluated. The rabbits were then killed to prepare the nerve specimens for histologic, immunohistochemical, and transmission electron microscope study. Results: At 4 months after the facial nerve repair, the functional recovery of the facial nerve was observed and analyzed. The side grafted with vascularized nerve graft was superior to the side grafted with free nerve graft. Regenerated nerve fibers were observed in all groups, and rabbits grafted with vascularized nerve grafts had more regenerated axons than those that underwent free nerve grafting, although the regenerated nerves were not as good as the natural nerves. Conclusions: This study demonstrates that it is feasible to establish a vascularized nerve graft model in rabbits. The model offers the obvious advantages of operability and reliability. The vascularized nerve graft is demonstrated to have a superior value for facial nerve repair.

Increased expression of MUC1 predicts poor survival in salivary gland mucoepidermoid carcinoma.

BACKGROUND Mucoepidermoid carcinoma (MEC) is a malignant neoplasm that originates most commonly in the major and minor salivary glands. The aim of this study is to determine the relationship between mucin-1 (MUC1) expression and patient outcome based on a large number of cases. PATIENTS AND METHODS Surgical specimens from 357 patients with primary salivary gland MEC and 10 patients with normal salivary gland tissue were examined by immunohistochemistry. The relationship between MUC1 expression and the clinicopathological data and patient survival was analyzed. RESULTS Results showed that MUC1 expression level was higher in MEC tissues than in paired normal tissues (P = 0.001), and the expression level of MUC1 was significantly associated with gender (P = 0.02), location (P = 0.001), grade (P = 0.001), stage (P = 0.0018) and lymph node metastasis (P = 0.001). In addition, increased expression of MUC1 was confirmed as a strong predictor of poor survival in salivary gland MEC (HR 2.175 [95% CI 1.263, 3.745]; P = 0.0051). CONCLUSION The findings indicate that an increased expression of MUC1 may be of great value in assessing the development and prognosis of salivary gland MEC, and could be used as a new molecule target to improve outcomes for these patients in the future.

Risk factors for postoperative delirium in patients undergoing major head and neck cancer surgery: a meta-analysis

Objective Postoperative delirium is common after extensive surgery. This study aimed to collate and synthesize published literature on risk factors for delirium in patients with head and neck cancer surgery. Methods Three databases were searched (MEDLINE, Embase, and Cochrane Library) between January 1987 and July 2016. The Newcastle Ottawa Scale (NOS) was adopted to evaluate the study quality. Pooled odds ratios or mean differences for individual risk factors were estimated using the Mantel-Haenszel and inverse-variance methods. Results They provided a total of 1940 patients (286 with delirium and 1654 without), and predominantly included patients undergoing head and neck cancer surgery. The incidence of postoperative delirium ranged from 11.50% to 36.11%. Ten statistically significant risk factors were identified in pooled analysis. Old age, age >70 years, male sex, duration of surgery, history of hypertension, blood transfusions, tracheotomy, American Society of Anesthesiologists physical status grade at least III, flap reconstruction and neck dissection were more likely to sustain delirium after head and neck cancer surgery. Conclusion Delirium is common in patients undergoing major head neck cancer surgery. Several risk factors were consistently associated with postoperative delirium. These factors help to highlight patients at risk of developing delirium and are suitable for preventive action.

Increased tumor-infiltrating plasmacytoid dendritic cells predicts poor prognosis in oral squamous cell carcinoma

OBJECTIVE Accumulating evidence suggests that plasmacytoid dendritic cells (pDC) have a dual role not only in initiating anti-tumor immune responses but also in inducing immune tolerance to facilitate cancer development. The aim of this study was to investigate the distribution and function of tumor-infiltrating pDCs in primary oral squamous cell carcinoma (OSCC) and their relation to patient outcome. METHODS The distribution of pDCs in 10 normal oral mucosa and 60 OSCC tissues was detected by immunohistochemistry. The population of pDCs in six OSCC patients and six healthy donors was evaluated by flow cytometry. The relationship between tumor-infiltrating pDCs and clinicopathological data and patient outcome was analyzed accordingly. The capacity of pDCs to produce cytokines, such as IFN-α, IL-6, IL-8 and TNF-α in response to TLR-9 ligands (CpG-ODN) was measured by ELISA. RESULT PDCs were detected at high levels in 38.3% of the OSCC tissues, primarily in the stroma, but were absent in normal oral mucosa. The frequency of pDCs in OSCC tissue was significantly higher than that observed in normal oral mucosa. However, the distribution and population of circulating pDCs was similar between healthy donors and OSCC patients. Kaplan-Meier analysis revealed a significant association of increasing number of tumor-infiltrating pDCs with lymph node metastasis and overall survival. Multivariate analysis confirmed that high levels of tumor-infiltrating pDCs was an independent prognostic factor. Further cytokine analysis revealed a decreased secretion of IFN-α, IL-6 and TNF-α, which indicated an impaired function of tumor-infiltrating pDCs. CONCLUSIONS The increased number of tumor-infiltrating pDCs correlates with an adverse outcome in primary OSCC patients. This finding is not only suggestive of the contribution of pDCs in the progression of oral cancer but also presents an opportunity and a new target for OSCC immune therapy in oral cancer management.

Inhibition of Protein Phosphatase 2A Sensitizes Mucoepidermoid Carcinoma to Chemotherapy via the PI3K-AKT Pathway in Response to Insulin Stimulus

Background/Aims: Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase that mediates cell cycle regulation and metabolism. Mounting evidence has indicated that PP2A inhibition exhibits considerable anticancer potency in multiple types of human cancers. However, the efficacy of PP2A inhibition remains unexplored in mucoepidermoid carcinoma (MEC), especially in locally advanced and metastatic cases with limited systemic treatment. In this study, we demonstrated the therapeutic potency of LB100 in mucoepidermoid carcinoma. Methods: In this study, the expression of PP2A was evaluated using immunohistochemical (IHC) staining. The effects associated with LB100 alone and in combination with cisplatin for the treatment of mucoepidermoid carcinoma were investigated both in vitro, regarding metabolism, proliferation, and migration, and in vivo in a mucoepidermoid carcinoma xenograft model. In addition, with LB100 treatment and in response to an insulin stimulus, the expression levels and phosphorylation levels of targets in the PI3K-AKT pathway were determined using western blot analysis and immunoblotting. Results: The expression of protein phosphatase 2A was significantly upregulated in the clinical specimens of high-grade MECs compared with those of low-/medium-grade MECs and normal controls. In this article, we report that a small molecule PP2A inhibitor, LB100, decreased cellular viability and glycolytic activity and induced G2/M cell cycle arrest. Importantly, LB100 enhanced the efficacy of cisplatin in mucoepidermoid carcinoma cells both in vitro and in vivo. PP2A inhibition by LB100 increased the phosphorylation of insulin receptor substrate 1(IRS-1) on serine residues, downregulated the expression of phosphatidylinositol 3-kinase (PI3K) p110 alpha subunit and dephosphorylated AKT at Ser473 and Thr308 in mucoepidermoid carcinoma cells in response to insulin stimulus. Conclusion: These results highlight the translational potential of PP2A inhibition to synergize with cisplatin in mucoepidermoid carcinoma treatment.

Prognostic and clinicopathological significance of MUC expression in head and neck cancer: a systematic review and meta-analysis

The prognostic value of mucins expression in patients with head and neck cancer (HNC) remains controversial. To address this, a meta-analysis was performed to systematically evaluate prognostic significance of mucins expression in HNC. Electronic and manual searches were performed and a total of 20 studies including 2046 patients were selected for the final analysis. Increased mucins expression was associated with unfavorable overall survival in HNC patients (HR=1.83, 95% CI: 1.43-2.33, p=0.000). Mucins overexpression was also in correlation with more advanced TNM stage (RR=0.84, 95% CI: 0.73-0.97, p=0.017), higher risk of lymph node metastasis (RR=0.69, 95% CI: 0.57-0.84, p=0.000) and deeper invasion (RR=0.58, 95% CI: 0.44-0.76, p=0.000). These results suggested that elevated mucins expression was significantly associated with worse prognosis and more detrimental clinicopathological outcomes, revealing the promising potential of mucins as biomarkers for HNC management.The prognostic value of mucins expression in patients with head and neck cancer (HNC) remains controversial. To address this, a meta-analysis was performed to systematically evaluate prognostic significance of mucins expression in HNC. Electronic and manual searches were performed and a total of 20 studies including 2046 patients were selected for the final analysis. Increased mucins expression was associated with unfavorable overall survival in HNC patients (HR=1.83, 95% CI: 1.43-2.33, p=0.000). Mucins overexpression was also in correlation with more advanced TNM stage (RR=0.84, 95% CI: 0.73-0.97, p=0.017), higher risk of lymph node metastasis (RR=0.69, 95% CI: 0.57-0.84, p=0.000) and deeper invasion (RR=0.58, 95% CI: 0.44-0.76, p=0.000). These results suggested that elevated mucins expression was significantly associated with worse prognosis and more detrimental clinicopathological outcomes, revealing the promising potential of mucins as biomarkers for HNC management.

Unexpected Extracardiac Multifocal Adult Rhabdomyomas With 10 Lesions of the Head and Neck: Epidemiology, Diagnosis, and Therapy

Adult rhabdomyomas (ARMs) are rare solitary benign neoplasms of the head and neck, and multifocal ARMs are even rarer. Owing to the low incidence and scanty knowledge of this peculiar entity, several patients have been reported to be misdiagnosed or overtreated. This report describes a patient with multifocal ARMs with as many as 10 synchronous lesions. In addition, all published cases of this entity in PubMed, Embase, and Web of Science databases were reviewed up to March 1, 2017. Overall, 10 of 29 reported cases had more than 2 lesions, with a maximum of 10 synchronous masses in the present report. Multifocal ARMs usually present as slow-growing lumps in the parapharyngeal region, with a predilection for older men. Treatments of multifocal ARMs should be tailored and close follow-up is recommended for tiny lesions located in vital structures. In addition, multifocal ARMs should be differentially diagnosed from other multifocal lesions in the head and neck region to avoid aggressive excision and produce a favorable outcome for patients.