Panoramic analysis of cell death patterns reveals prognostic and immune profiles of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) has been characterized by a low therapeutic response and poor prognosis. Currently, there are no reliable predictive models for HNSCC progression and therapeutic efficacy. This study explores the role of diverse patterns of cell death in tumor development, positing them as predictive factors of HNSCC prognosis. We utilized bulk transcriptome and single-cell transcriptome, align with clinical information from TCGA and GEO database, to analyze genes associated with 15 types of cell death and construct a cell death index (CDI) signature. The associations of CDI with tumor-infiltrating immune cells and immunotherapy-related biomarkers were also evaluated using various algorithms. The CDI signature emerged as a robust prognosis biomarker that could identify patients who can benefit potentially from immunotherapy, thus improving diagnostic accuracy and optimizing clinical decisions in HNSCC management. Notably, we discovered that CAAP1 deficiency not only induced apoptosis but also enhanced anti-tumor immunity, suggesting its potential as a target for clinical drug development.

Type 2 diabetes mellitus increases postoperative recurrence risk in Chinese patients with chronic rhinosinusitis.

BACKGROUND: The effect of type 2 diabetes mellitus (T2DM) on postoperative recurrence of chronic sinusitis (CRS) is unclear. OBJECTIVE: To investigate the association between T2DM and postoperative recurrence in CRS patients. METHODS: CRS patients who underwent surgery in our hospital from January 2018 to April 2020 were included and followed up for three years. Patients were classified into non-recurrent and recurrent CRS groups based on follow-up outcome, and logistic regression analysis was performed to identify risk factors for postoperative recurrence. RESULTS: A total of 412 CRS patients were included of whom 68 had T2DM. The postoperative recurrence rate was significantly higher in the T2DM group compared to the non-T2DM group (p < .05). T2DM prevalence and fasting blood glucose (FBG) levels were higher in recurrent CRS patients than those in non-recurrent CRS cases (p < .05). Multivariate regression analyses showed that age, duration of disease, FBG, and comorbid allergic rhinitis (AR) were significantly associated with an increased risk of postoperative recurrence of CRS (p < .05). Furthermore, adjusted logistic regression model revealed that T2DM was an independent risk factor for postoperative recurrence of CRS (p < .05). CONCLUSIONS: Elevated FBG levels may significantly influenced the postoperative recurrence of CRS in Chinese patients, and T2DM was an independent risk factor for recurrence.

[Nasal endoscopy assisting combined with transoral approach for resection of carcinoma of the palate invading nasal cavity and sinuses].

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.

Cetuximab enhances cisplatin-induced endoplasmic reticulum stress-associated apoptosis in laryngeal squamous cell carcinoma cells by inhibiting expression of TXNDC5.

Cisplatin and cetuximab, an anti­epidermal 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) stress­associated apoptosis. However, ER protein thioredoxin domain­containing protein 5 (TXNDC5) reportedly protects cells from ER stress­associated apoptosis. The present study investigated the interaction between cisplatin, cetuximab and TXNDC5 on ER stress­associated apoptosis in LSCC cells. AMC­HN­8 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 time­dependently increased and decreased the expression of TXNDC5 in AMC­HN­8 cells, respectively. Knockdown of TXNDC5 markedly augmented cisplatin­induced levels of CCAAT/enhancer­binding protein homologous protein (CHOP), caspase­3 activity and apoptosis; while overexpression of TXNDC5 largely eliminated cetuximab­induced levels of CHOP, caspase­3 activity and apoptosis. Cisplatin and cetuximab demonstrated a combinatorial effect on increasing the levels of CHOP, caspase­3 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 stress­associated apoptosis is a major mechanism underlying the apoptotic effect of cisplatin and cetuximab on LSCC cells; cetuximab enhanced cisplatin­induced ER stress­associated 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.

Hypoxia promotes migration/invasion and glycolysis in head and neck squamous cell carcinoma via an HIF-1α-MTDH loop.

Hypoxia is a hallmark of progressive cancer. Hypoxic cancer cells trigger glycolysis in response to a decreased O2 supply to meet metabolic and bioenergetic demands. Meanwhile, these responses to hypoxia and alterations of the microenvironment promote cancer cell metastasis by increasing transcription of hypoxia-inducible factor (HIF)-regulated genes. However, the detailed mechanism by which hypoxia regulates cancer cell metastasis and glycolysis remains to be investigated. In the present study, we identified that metadherin (MTDH), a multifaceted oncogene, is involved in the regulation of head and neck squamous cell carcinoma (HNSCC) metastasis and invasion under hypoxic conditions. Furthermore, the study indicated that there is a positive feedback loop between HIF-1α and MTDH in HNSCC cells, and that hypoxia promotes HNSCC cell metastasis and epithelial-mesenchymal transition by mediating the HIF-1α-MTDH loop. These findings implicate HIF-1α-MTDH as a promising target for anticancer drugs in solid tumors, and help to explain the pro-tumorigenic and unfavorable effect of MTDH on HNSCC observed in our previous studies.

Elevated expression of Derlin-1 associates with unfavorable survival time of squamous cell carcinoma of the head and neck and promotes its malignance.

Derlin-1 is over-expressed to function as an oncoprotein in breast, lung and colon cancers. However, the implications of Derlin-1 involved in squamous cell carcinoma of the head and neck (SCCHN) remain unknown. This study aims to investigate the effects of Derlin-1 expression on SCCHN tissues and cells. The potential mechanism of Derlin-1 regulating SCCHN cell proliferation, apoptosis and metastasis was also indicated in this work. Western blot and immunohistochemistry (IHC) assays showed that Derlin-1 was over-expressed in 114 SCCHN samples and five SCCHN cell lines. We found that the expression of Derlin-1 was positively associated with lymph node metastasis, clinical stage and recurrence in our SCCHN patients' samples. Survival analysis indicated that high expression of Derlin-1 was significantly associated with shorter overall survival (OS) and disease-free survival (DFS). Knock down expression of Derlin-1 in SCCHN cell lines was found to inhibit cell proliferation, metastasis and promote cell apoptosis. Further experiments showed that signals of PI3K/Akt, p53 and Smad2/3 may involve in these processes. In all, Derlin-1 might be a novel prognostic marker of SCCHN patients and plays an oncogenic role in SCCHN cell progression.

miR-23a promotes cisplatin chemoresistance and protects against cisplatin-induced apoptosis in tongue squamous cell carcinoma cells through Twist.

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.