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Background: Dosage-optimized multimodal radiotherapies that are safe for head and neck cancer patients are desirable. In this study, we investigated tissue tolerance to varying doses of external beam radiotherapy (EBRT) combined with low-dose rate brachytherapy in the neck of a rabbit model., Methods: Twenty rabbits were used in the four test groups (five each) with iodine-125 seeds implanted in the neck treated with EBRT in four doses at 50, 40, 30 and 20 Gy each. Twelve rabbits for three control groups (four each). Three months after implantation, all rabbits were euthanized, and target tissues were collected. Analyses included seed implantation assessment, histopathological evaluation, immunohistochemistry staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, electron microscopy and statistics with the SPSS software., Results: Five rabbits died in the four test groups, and three rabbits died in the three control groups (one per group), which showed no significant difference by survival analysis. The calculated minimum peripheral dose was 17.6 Gy, the maximum dose near the seed was 1812.5 Gy, the D90 was 34.5 Gy and the mean dose was 124.5 Gy. In all groups that received radiation, apoptosis occurred primarily in the esophageal mucosa and corresponded to the dose of radiation; a higher dose caused a greater apoptosis, with significant difference between groups (P < 0.05). Electron microscopy of carotid arteries revealed that endothelial cells were swollen and some were shed from basement membrane, but no other noticeable tissue damages., Conclusions: Limited EBRT at maximal dose (50 Gy) combined with the brachytherapy interstitially applied to the neck was tolerated well in the rabbit model., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Objectives: To evaluate the effectiveness of machine learning models based on morphological magnetic resonance imaging (MRI) radiomics in the classification of parotid tumors., Methods: In total, 298 patients with parotid tumors were randomly assigned to a training and test set at a ratio of 7:3. Radiomics features were extracted from the morphological MRI images and screened using the Select K Best and LASSO algorithm. Three-step machine learning models with XGBoost, SVM, and DT algorithms were developed to classify the parotid neoplasms into four subtypes. The ROC curve was used to measure the performance in each step. Diagnostic confusion matrices of these models were calculated for the test cohort and compared with those of the radiologists., Results: Six, twelve, and eight optimal features were selected in each step of the three-step process, respectively. XGBoost produced the highest area under the curve (AUC) for all three steps in the training cohort (0.857, 0.882, and 0.908, respectively), and for the first step in the test cohort (0.826), but produced slightly lower AUCs than SVM in the latter two steps in the test cohort (0.817 vs. 0.833, and 0.789 vs. 0.821, respectively). The total accuracies of XGBoost and SVM in the confusion matrices (70.8% and 59.6%) outperformed those of DT and the radiologist (46.1% and 49.2%)., Conclusion: This study demonstrated that machine learning models based on morphological MRI radiomics might be an assistive tool for parotid tumor classification, especially for preliminary screening in absence of more advanced scanning sequences, such as DWI., Key Points: • Machine learning algorithms combined with morphological MRI radiomics could be useful in the preliminary classification of parotid tumors. • XGBoost algorithm performed better than SVM and DT in subtype differentiation of parotid tumors, while DT seemed to have a poor validation performance. • Using morphological MRI only, the XGBoost and SVM algorithms outperformed radiologists in the four-type classification task for parotid tumors, thus making these models a useful assistant diagnostic tool in clinical practice., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Objective: To investigate the role of pre-treatment magnetic resonance imaging (MRI) radiomics for the preoperative prediction of lymph node (LN) metastasis in patients with hypopharyngeal squamous cell carcinoma (HPSCC)., Methods: A total of 155 patients with HPSCC were eligibly enrolled from single institution. Radiomics features were extracted from contrast-enhanced axial T-1 weighted (CE-T1WI) sequence. The most relevant features of LN metastasis were selected by the least absolute shrinkage and selection operator (LASSO) method. Univariate and multivariate logistic regression analysis was adopted to determine the independent clinical risk factors. Three models were constructed to predict the LN metastasis status: one using radiomics only, one using clinical factors only, and the other one combined radiomics and clinical factors. Receiver operating characteristic (ROC) curves and calibration curve were used to evaluate the discrimination and the accuracy of the models, respectively. The performances were tested by an internal validation cohort (n=47). The clinical utility of the models was assessed by decision curve analysis., Results: The nomogram consisted of radiomics scores and the MRI-reported LN status showed satisfactory discrimination in the training and validation cohorts with AUCs of 0.906 (95% CI, 0.840 to 0.972) and 0.853 (95% CI, 0.739 to 0.966), respectively. The nomogram, i.e., the combined model, outperformed the radiomics and MRI-reported LN status in both discrimination and clinical usefulness., Conclusions: The MRI-based radiomics nomogram holds promise for individual and non-invasive prediction of LN metastasis in patients with HPSCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lu, Ling, Chen, Tan, Gao, Li, Tan, Huang, Zhang, Liu, Mao and Qiu.)

Objective: To explore whether radiomics features extracted from pre-treatment magnetic resonance imaging (MRI) can predict the overall survival (OS) in patients with hypopharyngeal squamous cell carcinoma., Methods: A total of 190 patients with hypopharyngeal squamous cell carcinoma were eligibly enrolled from two institutions. Radiomics features were extracted from contrast-enhanced axial T1-weighted (CE-T1WI) sequence. The least absolute shrinkage selection operator (LASSO) algorithm was applied to establish a radiomics score correlated with OS. Multivariate logistic regression analysis was applied to determine the independent risk factors, which was combined with radiomics score to build the final radiomics nomogram., Results: A radiomics score with 6 CE-T1WI features for OS prediction was constructed and validated; its integration with specific clinicopathologic factors (N stage) showed a better prediction performance in the training, internal validation, and external validation cohorts (C-index 0.78, 0.75, and 0.75). Calibration curves determined a good agreement between the predicted and actual overall survival., Conclusions: The radiomics-clinical nomogram and radiomics score might be non-invasive and reliable methods for the risk stratification in patients with hypopharyngeal squamous cell carcinoma., Key Points: • An MRI-based radiomics model was constructed to evaluate of OS in patients with hypopharyngeal squamous cell carcinoma. • A radiomics-clinical nomogram that combined radiomics features and clinical characteristics was established. • Multi-cohort study validated the predictive performance of the radiomics-clinical nomogram to stratify patients with high risk in clinical practice., (© 2021. European Society of Radiology.)

Objective: To explore the value of nasal endoscopy assisting combined with transoral approach in resection of the carcinoma of the palate with the nasal cavity and sinuses invaded. Methods: A retrospective analysis of 21 patients with a primary malignant tumors of the palate was performed. Preoperative nasal endoscopy and CT and MRI scan showed that the primary tumors invading the nasal cavity and sinuses in all patients or skull base with varying degrees. All patients were treated by nasal endoscopic assisting combined with transoral approach. Postoprational adjuvant radiotherapy or concurrent chemoradiotherapy was performed according to pathological types and clinical stage. Postoperative complications, all-tumor resection rate, local control rate and 5-year survival rate were analyzed statistically. Results: The combined approach was successfully performed in all patients. En bloc resection was carried out in 18 patients by this combined approach and surgical margins were free of carcinoma. The median follow-up period was 60 months. All patients had good nasal ventilation function and no epiphora in postoperation, and the overall local control rate of primary site was 85.7%, overall 5-year survival rate was 76.2%. Conclusion: Nasal endoscopy assisting combined with transoral approach is an effective method for the resection of palate malignant tumors invading the nasal cavity and sinuses. It is convenient for en bloc resection and local control of primary lesions. It is beneficial to preserve the function of nasal cavity and sinuses, which is in line with the principle of functional surgery., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Squamous cell carcinoma (SCC) is an aggressive malignancy that can originate from various organs. TP63 is a master regulator that plays an essential role in epidermal differentiation. It is also a lineage-dependent oncogene in SCC. ΔNp63α is the prominent isoform of TP63 expressed in epidermal cells and SCC, and overexpression promotes SCC development through a variety of mechanisms. Recently, ΔNp63α was highlighted to act as an epidermal-specific pioneer factor that binds closed chromatin and enhances chromatin accessibility at epidermal enhancers. ΔNp63α coordinates chromatin-remodeling enzymes to orchestrate the tissue-specific enhancer landscape and three-dimensional high-order architecture of chromatin. Moreover, ΔNp63α establishes squamous-like enhancer landscapes to drive oncogenic target expression during SCC development. Importantly, ΔNp63α acts as an upstream regulator of super enhancers to activate a number of oncogenic transcripts linked to poor prognosis in SCC. Mechanistically, ΔNp63α activates genes transcription through physically interacting with a number of epigenetic modulators to establish enhancers and enhance chromatin accessibility. In contrast, ΔNp63α also represses gene transcription via interacting with repressive epigenetic regulators. ΔNp63α expression is regulated at multiple levels, including transcriptional, post-transcriptional, and post-translational levels. In this review, we summarize recent advances of p63 in epigenomic and transcriptional control, as well as the mechanistic regulation of p63.

Head and neck squamous cell carcinoma (HNSCC) constitute approximately 4% of all cancers worldwide. In this study, we analyzed the expression profile of the long noncoding RNA (lncRNA) of 502 HNSCC patients from The Cancer Genome Atlas database. Among the differentially expressed lncRNAs between HNSCC and normal samples, LNCAROD is overexpressed in HNSCC and associated with advanced T stage and shortened overall survival. The N6-methyladenosine (m6A) modification mediated by METTL3 and METTL14 enhanced the stability of LNCAROD in HNSCC cells. Depletion of LNCAROD attenuated cell proliferation, mobility in vitro, and tumorigenicity in vivo, whereas overexpression of LNCAROD exerted opposite effects. LNCAROD is mainly distributed in nucleus and binds with YBX1 and HSPA1A proteins. Silencing either YBX1 or HSPA1A did not affect the level of LNCAROD. However, loss of LNCAROD led to shortened half-life of YBX1 protein. Mechanistically, LNCAROD protected YBX1 from proteasomal degradation by facilitating YBX1-HSPA1A protein-protein interaction. Depletion of HSPA1A in LNCAROD-overexpressing cells resulted in accelerated proteasomal degradation of YBX1 protein. Moreover, re-expression of Flag-YBX1 in LNCAROD-silenced cells rescued malignant behavior of HNSCC cells. Our study indicates that LNCAROD is an oncogenic lncRNA and dysregulation of m6A modification might account for aberrant expression of LNCAROD in HNSCC. LNCAROD acts as a scaffold for the interaction between YBX1 and HSPA1A, preventing proteasomal degradation of YBX1 in HNSCC cells., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Invasion and metastasis represent the primary causes of therapeutic failure in patients diagnosed with squamous cell carcinoma of the head and neck (SCCHN). Therefore, disease prediction and inhibition of invasion and metastasis are critical for enhancing the survival of patients with SCCHN. Our previous study revealed that increased expression of miR-93-5p is associated with poor prognosis in SCCHN; however, the mechanism underlying the oncogenic functions of miR-93-5p in SCCHN migration and invasion remains unclear. Using qPCR analyses, transwell assays, and scratch tests, we demonstrated that expression of ectopic miR-93-5p induced the migration and invasion of SCCHN, and this was accompanied by corresponding alterations in biomarkers and transcription factors specific for epithelial-mesenchymal transition (EMT). Luciferase reporter assays were used to demonstrate that miR-93-5p directly targeted the 3' UTR of RGMB, and we further found that the tumor-promoting functions of miR-93-5p were partly mediated by targeting RGMB, whose downregulation also promoted the migration and invasion of SCCHN. Overall, our results indicate that miR-93-5p acts as an oncogene in the regulation of migration and invasion by suppressing RGMB in SCCHN. These findings provide novel evidence that miR-93-5p may serve as a valuable predictive biomarker and potential intervention target in patients with SCCHN., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Metastasis is a critical determinant for the treatment strategy and prognosis in patients with squamous cell carcinoma of the head and neck (SCCHN). However, the mechanisms underlying SCCHN metastasis are poorly understood. Our study sought to determine the key microRNA and their functional mechanisms involved in SCCHN metastasis. For The Cancer Genome Atlas (TCGA) data analysis, quantitative PCR was used to quantify the level of miR-30e-5p in SCCHN and its clinical significance was further analyzed. A series of in vitro and in vivo experiments were applied to determine the effects of miR-30e-5p and its target AEG-1 on SCCHN metastasis. A mechanism investigation further revealed that AEG-1 was implicated in the angiogenesis and metastasis mediated by miR-30e-5p. Overall, our study confirms that miR-30e-5p is a valuable predictive biomarker and potential therapeutic target in SCCHN metastasis., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common type of cancer around the world. The aim of this study was to seek the long non-coding RNAs (lncRNAs) acting as diagnostic and prognostic biomarker of HNSCC., Methods: Base on TCGA dataset, the differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) were identified between HNSCC and normal tissue. The machine learning and survival analysis were performed to estimate the potential diagnostic and prognostic value of lncRNAs for HNSCC. We also build the co-expression network and functional annotation. The expression of selected candidate mRNAs and lncRNAs were validated by Quantitative real time polymerase chain reaction (qRT-PCR)., Results: A total of 3363 DEmRNAs (1822 down-regulated and 1541 up-regulated mRNAs) and 32 DElncRNAs (13 down-regulated and 19 up-regulated lncRNAs) between HNSCC and normal tissue were obtained. A total of 13 lncRNAs (IL12A.AS1, RP11.159F24.6, RP11.863P13.3, LINC00941, FOXCUT, RNF144A.AS1, RP11.218E20.3, HCG22, HAGLROS, LINC01615, RP11.351J23.1, AC024592.9 and MIR9.3HG) were defined as optimal diagnostic lncRNAs biomarkers for HNSCC. The area under curve (AUC) of the support vector machine (SVM) model, decision tree model and random forests model and were 0.983, 0.842 and 0.983, and the specificity and sensitivity of the three model were 95.5% and 96.2%, 77.3% and 97.6% and 93.2% and 97.8%, respectively. Among them, AC024592.9, LINC00941, LINC01615 and MIR9-3HG was not only an optimal diagnostic lncRNAs biomarkers, but also related to survival time. The focal adhesion, ECM-receptor interaction, pathways in cancer and cytokine-cytokine receptor interaction were four significantly enriched pathways in DEmRNAs co-expressed with the identified optimal diagnostic lncRNAs. But for most of the selected DEmRNAs and DElncRNAs, the expression was consistent with our integrated analysis results, including LINC00941, LINC01615, FOXCUT, TGA6 and MMP13., Conclusion: AC024592.9, LINC00941, LINC01615 and MIR9-3HG was not only an optimal diagnostic lncRNAs biomarkers, but also were a prognostic lncRNAs biomarkers.

CCL18 is a cytokine secreted by M2 type tumor associated macrophages, which frequently over-expressed in diverse human cancers. However, the clinical significance of serum CCL18 in patients with laryngeal squamous cell carcinoma (LSCC) remains unknown. In this study, serum CCL18 was initially quantified by enzyme-linked immunosorbent assay (ELISA) in 146 patients with LSCC, 25 patients with precancerous lesions and 72 healthy volunteers. In addition, the correlations between serum CCL18 and clinicopathological parameters were analyzed. Our data revealed that serum CCL18 was obviously increased in patients with LSCC. Moreover, serum CCL18 level was significantly associated with primary tumor site (Glottic vs Others), T classification (T1+T2 vs T3+T4), clinical stage (I+II vs III+IV) and lymph node metastasis (N0 vs N+). Survival analysis demonstrated that patients with high serum CCL18 displayed a shorter survival time than those in patients with low serum CCL18. Importantly, serum CCL18 level and clinical stage were independent prognostic factors in patients with LSCC. Taken together, serum CCL18 could be used as a promising biomarker in patients with LSCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

As a classical ligand in the canonical Wnt/β-catenin signaling pathway, the role of Wnt3a in laryngeal squamous cell carcinoma (LSCC) remains unclear. Therefore, the expression pattern of the Wnt3a protein in 222 primary LSCC, and 19 corresponding adjacent non-carcinoma specimens, was detected by immunohistochemistry and further correlated with clinicopathological parameters. The results showed that LSCC tissue expressed higher levels of the Wnt3a protein when compared to the corresponding adjacent non-cancerous tissues. High expression of Wnt3a was closely related to histological grade (P = 0.031), clinical stage (I+II / III+IV; P = 0.004), and lymph node metastasis (P = 0.03). Kaplan-Meier analysis evidenced that a worse overall survival (OS) was correlated to the group with high Wnt3a expression (P = 0.003). When stratified survival analyses were performed, patients with lymph node metastasis/advanced clinical stages and high Wnt3a expression had worse OS rates than patients with other features (P < 0.001). Finally, multivariate analysis showed that Wnt3a expression was an independent prognosis factor for LSCC patients. The current findings suggest that Wnt3a is tightly related to the LSCC progression and could serve as a valuable clinic biomarker for LSCC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The canonical Wnt/β-catenin signalling pathway and autophagy play critical roles in cancer progression. However, the role of Wnt-mediated autophagy in cancer radioresistance remains unclear. In this study, we found that irradiation activated the Wnt/β-catenin and autophagic signalling pathways in squamous cell carcinoma of the head and neck (SCCHN). Wnt3a is a classical ligand that activated the Wnt/β-catenin signalling pathway, induced autophagy and decreased the sensitivity of SCCHN to irradiation both in vitro and in vivo. Further mechanistic analysis revealed that Wnt3a promoted SCCHN radioresistance via protective autophagy. Finally, expression of the Wnt3a protein was elevated in both SCCHN tissues and patients' serum. Patients showing high expression of Wnt3a displayed a worse prognosis. Taken together, our study indicates that both the canonical Wnt and autophagic signalling pathways are valuable targets for sensitizing SCCHN to irradiation., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Cisplatin and cetuximab, an anti‑epidermal growth factor receptor (EGFR) monoclonal humanized antibody, have been used for treatment of laryngeal squamous cell carcinoma (LSCC). It has been demonstrated that cisplatin and inhibition of EGFR signaling may induce endoplasmic reticulum (ER) stress‑associated apoptosis. However, ER protein thioredoxin domain‑containing protein 5 (TXNDC5) reportedly protects cells from ER stress‑associated apoptosis. The present study investigated the interaction between cisplatin, cetuximab and TXNDC5 on ER stress‑associated apoptosis in LSCC cells. AMC‑HN‑8 human LSCC cells with or without TXNDC5 overexpression or knockdown were treated with cisplatin (5, 10, 20 and 40 µM) and/or cetuximab (10, 50, 100 and 150 µg/ml), for 12, 24, 36 and 48 h. Cisplatin and cetuximab concentration‑ and time‑dependently increased and decreased the expression of TXNDC5 in AMC‑HN‑8 cells, respectively. Knockdown of TXNDC5 markedly augmented cisplatin‑induced levels of CCAAT/enhancer‑binding protein homologous protein (CHOP), caspase‑3 activity and apoptosis; while overexpression of TXNDC5 largely eliminated cetuximab‑induced levels of CHOP, caspase‑3 activity and apoptosis. Cisplatin and cetuximab demonstrated a combinatorial effect on increasing the levels of CHOP, caspase‑3 activity and apoptosis, which was largely eliminated by overexpression of TXNDC5 or a reactive oxygen species (ROS) scavenger/antagonist. In addition, promoter/luciferase reporter assays revealed that cisplatin and cetuximab regulated the expression of TXNDC5 at the gene transcription/promoter level. In conclusion, the findings suggested that ER stress‑associated apoptosis is a major mechanism underlying the apoptotic effect of cisplatin and cetuximab on LSCC cells; cetuximab enhanced cisplatin‑induced ER stress‑associated apoptosis in LSCC cells largely by inhibiting the expression of TXNDC5 and thereby increasing ROS production; cisplatin and cetuximab had stimulatory and inhibitory effects on the TXNDC5 gene promoter, respectively. The present study offered novel insights into the pharmacological effects of cisplatin and cetuximab on LSCC. It also suggested that TXNDC5 may be a potential therapeutic target for LSCC.

Purpose: MicroRNAs function through regulating specific target mRNA expression and then participate in the development and progression of diverse human cancers. MiR-98 shows aberrant expression and dysfunction in tumors. However, its clinical significance and exact role in squamous cell carcinoma of the head and neck (SCCHN) remain elusive., Methods: MiR-98 expression was examined by qRT-PCR and correlated with clinicopathological variables and prognosis in SCCHN patients. Effects of miR-98 on epithelial-mesenchymal transition (EMT) and the malignant phenotypes of SCCHN were studied. Finally, the role of target gene metadherin (MTDH) in miR-98 mediated effects were assayed., Results: Our results demonstrated that miR-98, as an endogenous inhibitor of MTDH via directly binding to its 3'-untranslated region (UTR) region, decreased significantly in SCCHN tissues. Decreased miR-98 expression was negatively correlated with T classification, clinical stage, lymph node metastasis and a shorter survival status in SCCHN patients. Loss-of-function and gain-of-function analyses confirmed that miR-98 inhibited cell proliferation, migration and invasion of SCCHN cells in vitro . Moreover, miR-98 repression led to increased MTDH expression and induced EMT alteration. Importantly, ectopic expression of MTDH partially reversed the effects caused by miR-98 overexpression., Conclusions: Our study identifies that miR-98 serves as a suppressor in SCCHN progression via targeting oncogene MTDH ., Competing Interests: None.

Objective: This study aimd to evaluate the application and clinical effect of improved submental island flap in hypopharyngeal cancer reserved laryngeal function surgery., Method: A retrospective review of clinical data was performed on 38 patients of hypopharyngeal cancer reserved laryngeal function using sumental island flaps, by the way of improving in design of vascular pedicle, reconstructive mode of laryngeal and hypopharyngeal function and closing of wound of neck following hypopharyngeal cancer resection. Meanwhile, the effect and prognosis was comprehensively assessed on patients with hypopharyngeal cancer reserved laryngeal function using improved submental island flaps., Result: The submental flaps kept alive in all 38 cases. During the follow-up period, 18 cases were dead, and of them, 7 cases died of the second primary carcinoma, included 4 cases of esophagus cancer, 1 case of cancer of soft palate, 2 cases of nasopharyngeal carcinoma; and 5 cases died of cervical or parapharyngeal lymph nodes recurrence; 2 cases died of hepatic metastasis; and 4 cases died of pulmonary metastasis. The overall 5-years survival rate was 52.6%., Conclusion: Improved submental island flap repairing postoperative defect of hypopharyngeal cancer reserved laryngeal function has many advantages including higher success rate, more security, easy and simple to operate as well as good clinical effects, and is worth to widespread using.

Tongue squamous cell carcinoma (TSCC) is one of the most common head and neck cancers. Cisplatin is effective as a single agent or in combination with other drugs for the treatment of TSCC. Treatment with cisplatin-based chemotherapy has been found to improve the prognosis of patients with TSCC. However, one of the most important clinical issues of cisplatin-based TSCC chemotherapy is the intrinsic/acquired chemoresistance to cisplatin. Increased expression of miR-23a reportedly promotes cisplatin chemoresistance in TSCC cells. High expression of Twist is also associated with cancer chemoresistance and poor prognosis of TSCC patients. In the present study, we explored the interaction between miR-23a and Twist in TSCC cells, and assessed its impact on TSCC chemoresistance to cisplatin. miR-23a and/or Twist were overexpressed or knocked down in SCC-4 and Tca8113 human TSCC cells. The expression levels of miR-23a and Twist were determined. The half maximal inhibitory concentration (IC50) of cisplatin and cell apoptosis rate under cisplatin treatment were used as measures of cisplatin chemoresistance. Overexpression of miR-23a in both SCC-4 and Tca8113 cells markedly increased Twist expression, c-Jun N-terminal kinase (JNK) activity and the half maximal inhibitory concentration (IC50) of cisplain, and decreased cisplatin-induced apoptosis, all of which was abolished by knockdown of Twist or selective JNK inhibitor SP600125. On the other hand, knockdown of miR-23a significantly decreased Twist expression, JNK activity and IC50 of cisplain, and increased cisplatin-induced apoptosis, all of which was completely reversed by overexpression of Twist. In conclusion, the present study for the first time demonstrates that miR-23a promotes cisplatin chemoresistance and protects cisplatin-induced apoptosis in TSCC cells through inducing Twist expression by a JNK-dependent mechanism. It adds new insights into the molecular mechanisms underlying TSCC chemoresistance.

Ephrin type‑A receptor 2 (EphA2) is a receptor tyrosine kinase that is associated with cancer cell metastasis. There has been little investigation into its impact on the regulation of sensitivity to paclitaxel in nasopharyngeal carcinoma (NPC). In the present study, upregulation of EphA2 expression enhanced the survival of NPC 5‑8F cells, compared with control cells exposed to the same concentrations of paclitaxel. Flow cytometry and western blot analysis demonstrated that over‑expression of EphA2 decreased NPC cancer cell sensitivity to paclitaxel by regulating paclitaxel‑mediated cell cycle progression but not apoptosis in vitro. This was accompanied by alterations in the expression of cyclin‑dependent kinase inhibitors, p21 and p27, and of inactive phosphorylated‑retinoblastoma protein. Furthermore, paclitaxel stimulation and EphA2 over‑expression resulted in activation of the phosphoinositide 3‑kinase (PI3K)/Akt signalling pathway in NPC cells. Inhibition of the PI3K/Akt signalling pathway restored sensitivity to paclitaxel in 5‑8F cells over‑expressing EphA2, which indicated that the PI3K/Akt pathway is involved in EphA2‑mediated paclitaxel sensitivity. The current study demonstrated that EphA2 mediates sensitivity to paclitaxel via the regulation of the PI3K/Akt signalling pathway in NPC.

EphA2 is frequently overexpressed and functionally altered in a variety of human cancers. However, its roles in human nasopharyngeal carcinoma (NPC) remain unclear. To investigate the roles of EphA2 in the development and progression of NPC, we initially evaluated the expression pattern of EphA2 protein in NPC tissues using western blotting and CCK-8 assay. Fluorescence-activated cell sorting analysis and invasion assay were conducted to observe the effects of EphA2 inhibition in vivo. Our results demonstrated that EphA2 was overexpressed in NPC specimens and the expression of EphA2 was significantly associated with T classification, advanced clinical stage and lymph node metastasis. Moreover, human NPC 5-8F cells were infected with lentiviral vector-mediated EphA2-specific shRNA, which resulted in the significant inhibition of cell growth, invasion of 5-8F cells and markedly enhanced the sensitivity of 5-8F cells to the chemotherapeutic agent paclitaxel in vitro . Collectively, our results demonstrate that EphA2 is involved in malignant cell behavior and is a potential therapeutic target in human NPC.

ERp29 is an endoplasmic reticulum (ER) stress-inducible protein. It was found that ERp29 was highly expressed in several cancers and associated with resistance to oxidative and radiation stress, which may serve as a novel target for nasopharyngeal carcinoma (NPC) anticancer approach. In this study, we used immunohistochemistry to detect ERp29 expression in radioresistant and radiosensitive NPC tissues. As a result, ERp29 was up-regulated in radioresistant NPC tissues compared to radiosensitive NPC tissues. We also found that ERp29 knockdown attenuated radioresistance of NPC CNE-1 cells and ERp29 overexpression enhanced radioresistance of NPC CNE-2 cells. When exposed to radiation, ERp29 knockdown CNE-1 cells increased radiation-induced cell apoptosis and ERp29 overexpression CNE-2 cells reduced radiation-induced cell apoptosis. Further, we demonstrated that ERp29 up-regulated the expression of Hsp27. In conclusion, our study supports ERp29 could potentiate resistance to radiation in NPC cells, targeting of ERp29 is a rational strategy in treating radioresistant NPC.

Objective: To investigate the synergistic cytotoxicity of TRAIL and paclitaxel on nasopharyngeal cell lines CNE-1 and CNE-2., Method: CCK-8 assays the growth inhibition rate of CNE-1 and CNE-2 which was treated with TRAIL or paclitaxel or combination of both. Flow cytometry tests the apoptosis rate of CNE-1 and CNE-2 which was treated with TRAIL or paclitaxel or combination of each other., Result: In certain range of time and concentration,TRAIL and paclitaxel inhibited the growth of the cell lines of CNE-1 and CNE-2 in a time-dose dependent manner (P < 0.05). The rate of growth inhibition and apoptosis in TRAIL and paclitaxel combinative group was more significant than that in the TRAIL and paclitaxel singular group (P < 0.05)., Conclusion: TRAIL and paclitaxel had a synergistic killing effect on NPC cell lines and showed better affection than singular group, which provides a novel and prospective strategy for NPC chemotherapy.

Objective: To investigate the expression and biological significance of HMGB1 and VEGF protein in tissue specimens of laryngeal squamous cell carcinoma (LSCC), and further study the correlation between HMGB1 and VEGF protein., Method: The expression of HMGB1 and VEGF protein was evaluated by immunohistochemical staining in 69 cases of LSCC specimens and 15 cases of adjacent epithelial tissue samples, and futher correlated with clinicopathologic parameters., Result: The positive rates of HMGB1 and VEGF in LSCC tissues were significantly higher than those in adjacent non-cancerous mucosa (P < 0.01), and the expression of these two marks was closely correlated with clinical stage (P < 0.05) and metastasis (P < 0.05) in LSCC. While the expression of HMGB1 and VEGF had no significant correlations with age, sex, histological differentiation and tumor site (P > 0. 05). There was a positive correlation between the expression of HMGB1 and VEGF (P < 0.05). The Kaplan-Meier survival analysis showed that patients with strong expression of HMGB1 or VEGF had poorer overall survival compared with that in patients with relative low HMGB1 or VEGF expression (P < 0.05). Multivariate COX regression analysis revealed that both lymph node metastasis and HMGB1 expression were independent prognostic factors for patients with LSCC., Conclusion: This study demonstrated that HMGB1 and VEGF protein overexpression were closely associated with clinical stage, metastasis and poorer prognosis in patients with LSCC. Increased expression of these two proteins in LSCC suggested that HMGB1 and VEGF might play a critical role in the initiation and progression of LSCC.

Purpose: HMGB1 overexpression has been reported in a variety of human cancers. However, the role of HMGB1 in squamous-cell carcinoma of the head and neck (SCCHN) remains unclear. The aim of the present investigation was to analyse HMGB1 protein expression in both SCCHN tissue and cell levels and to assess its prognostic significance in SCCHN., Methods: HMGB1 protein expression in 103 primary SCCHN tissue specimens was analysed by immunohistochemistry and correlated with clinicopathological parameters and patient outcome. Additionally, HMGB1 protein expression was evaluated in cell level by Western blotting., Results: By Western blotting analysis, all the 5 SCCHN cell lines overexpressed HMGB1 protein, whereas the non-transformed immortalised cell line NP-69 had relatively weak HMGB1 protein expression. Immunohistochemical staining revealed that HMGB1 protein was detected in 91 (91/103, 88.3%) primary tumour samples, but only in 7 (7/16, 43.75%) adjacent non-carcinoma samples (p<0.001); moreover, HMGB1 overexpression was significantly associated with T classification (p=0.001), clinical stage (p<0.001), recurrence (p<0.001) and lymph node metastasis (p<0.001). Survival analysis demonstrated that high HMGB1 expression was significantly associated with shorter disease-free and overall survival (both p<0.001), especially in late patients with SCCHN. When HMGB1 expression and lymph node status were combined, patients with HMGB1 overexpression/lymph node (+) had both poorer disease-free and overall survival than others (both p<0.001). Multivariate analysis further demonstrated that HMGB1 was an independent prognostic factor for patients with SCCHN., Conclusions: HMGB1 protein may contribute to the malignant progression of SCCHN, and present as a novel prognostic marker and a potential therapeutic target for patients with SCCHN., (Copyright © 2010 Elsevier Ltd. All rights reserved.)