Temporal and spatial patterns of recurrence in oral squamous cell carcinoma, a single-center retrospective cohort study in China.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is an invasive cancer with a high recurrence rate. Most clinical studies have focused on the prognosis of patients with OSCC, few have investigated the causes and interventions that affect the recurrence. Our study is to explore the temporal and spatial patterns of recurrence in OSCC. METHODS: 234 OSCC patients with recurrence in our hospital and 64 OSCC patients with recurrence in TCGA database were included in the study. Log-rank test and Multivariate Cox Regression Analysis were used to determine whether there was a significant difference between each selected demographic or clinical factors and recurrence. The Kaplan-Meier method was used to plot survival curves for each recurrence interval. RESULTS: The proportion of OSCC patients in clinical and TCGA with early recurrence was 93.6% and 84.4%, respectively. Age, chewing betel nut, previous radiotherapy, histopathological grading of the primary tumor (poorly differentiated), lymph node metastasis and postoperative infection were found to be associated with the timing of recurrence. It was found that tongue cancer has more regional recurrences, while buccal cancer is mostly local and loco-regional recurrences. The earlier the recurrence, the greater the possibility of local-regional recurrence and the worse the prognosis. CONCLUSION: Most of recurrent OSCC patients present early recurrence (< 18 months) with poor prognosis, and early recurrence is more prone to local recurrence. Moreover, recurrence site is related with primary site of OSCC.

Risk factors for surgical site infection in head and neck cancer.

PURPOSE: Surgical site infection (SSI) frequently occurs in patients with head and neck cancer (HNC) after tumor resection and can lead to death in severe cases. Moreover, there is no definitive conclusion about the risk factors of SSI. Therefore, it is of great clinical significance to study the factors affecting the SSI. METHODS: The HNC patients included in this study were all from the Department of Oral and Maxillofacial Surgery of the Second Xiangya Hospital of Central South University (CSU), and these patients received surgical treatment in the department from January 2018 to December 2019. The cross tabulation with chi-squared testing and multivariate regression analysis were applied to determine the risk factors of SSI. To identify the key risk factors of SSI, the caret package was used to construct three different machine learning models to investigate important features involving 26 SSI-related risk factors. RESULTS: Participants were 632 HNC patients who underwent surgery in our department from January 2018 to December 2019. During the postoperative period, 82 patients suffered from SSI, and surgical site infection rate (SSIR) was about 12.97%. Multivariate logistic regression analysis shows that diabetes mellitus, primary tumor site (floor of mouth), preoperative radiotherapy, flap failure, and neck dissection (bilateral) are risk factors for SSI of HNC. Machine learning indicated that diabetes mellitus, primary tumor site (floor of mouth), and flap failure were consistently ranked the top three in the 26 SSI-related risk factors. CONCLUSION: Diabetes mellitus, primary tumor site (floor of mouth), flap failure, preoperative radiotherapy, and neck dissection (bilateral) are risk factors for SSI of HNC.

Perioperative mortality of head and neck cancers.

BACKGROUND: Head and neck cancers are aggressive cancers, most clinical studies focused on the prognosis of patients with head and neck cancer. However, perioperative mortality was rarely mentioned. METHODS: A retrospective analysis was performed using all head and neck cancer patients admitting in the Department of Oral and Maxillofacial Surgery of the Second Xiangya Hospital, Central South University from January 2010 to December 2019. The analysis of overall survival and progression-free survival were performed using the Kaplan-Meier method, and cross tabulation with chi-squared testing was applied to analyze the difference in parameters between groups. RESULTS: From January 2010 to December 2019, a total of 6576 patients with head and neck cancers were admitted to our department and 7 died in the hospital, all of whom were middle-aged and elderly patients including 6 males and 1 female. The perioperative mortality rate (POMR) was about 1‰. The causes of death included acute heart failure, rupture of large blood vessels in the neck, hypoxic ischemic encephalopathy due to asphyxia, respiratory failure and cardiopulmonary arrest. CONCLUSION: Preoperative radiotherapy, previous chemotherapy, hypertension, diabetes, advanced clinical stage and postoperative infection are risk factors for perioperative mortality of head and neck cancer.

Synovial sarcoma of the floor of the mouth: a rare case report.

BACKGROUND: Head and neck Synovial sarcoma (SS) accounts for 3-10% of all total body SS. It is rare to find it in the oral cavity, especially on the floor of the mouth. CASE PRESENTATION: We present a 44-year-old Chinese male, who had been misdiagnosed as fibroadenoma, with a swelling on the right submandibular region for more than 3 months. The radiology examinations and the pathology results indicate the diagnosis of SS of the floor of the mouth. The patient only had a surgical operation, without radiotherapy and chemotherapy. At the first follow-up, the patient exhibited no clinical or radiographic complications, and the patient was asymptomatic on subsequent visits. CONCLUSIONS: Misdiagnosis results the delay of diagnosis and treatment of SS. Immunohistological analysis might be the most important tool to confirm the diagnosis of SS.

Inhibiting MT2-TFE3-dependent autophagy enhances melatonin-induced apoptosis in tongue squamous cell carcinoma.

Autophagy modulation is a potential therapeutic strategy for tongue squamous cell carcinoma (TSCC). Melatonin possesses significant anticarcinogenic activity. However, whether melatonin induces autophagy and its roles in cell death in TSCC are unclear. Herein, we show that melatonin induced significant apoptosis in the TSCC cell line Cal27. Apart from the induction of apoptosis, we demonstrated that melatonin-induced autophagic flux in Cal27 cells as evidenced by the formation of GFP-LC3 puncta, and the upregulation of LC3-II and downregulation of SQSTM1/P62. Moreover, pharmacological or genetic blockage of autophagy enhanced melatonin-induced apoptosis, indicating a cytoprotective role of autophagy in melatonin-treated Cal27 cells. Mechanistically, melatonin induced TFE3(Ser321) dephosphorylation, subsequently activated TFE3 nuclear translocation, and increased TFE3 reporter activity, which contributed to the expression of autophagy-related genes and lysosomal biogenesis. Luzindole, a melatonin membrane receptor blocker, or MT2-siRNA partially blocked the ability of melatonin to promote mTORC1/TFE3 signaling. Furthermore, we verified in a xenograft mouse model that melatonin with hydroxychloroquine or TFE3-siRNA exerted a synergistic antitumor effect by inhibiting autophagy. Importantly, TFE3 expression positively correlated with TSCC development and poor prognosis in patients. Collectively, we demonstrated that the melatonin-induced increase in TFE3-dependent autophagy is mediated through the melatonin membrane receptor in TSCC. These data also suggest that blocking melatonin membrane receptor-TFE3-dependent autophagy to enhance the activity of melatonin warrants further attention as a treatment strategy for TSCC.

A regulatory mechanism of a stepwise osteogenesis-mimicking decellularized extracellular matrix on the osteogenic differentiation of bone marrow-derived mesenchymal stem cells.

A cell-derived decellularized extracellular matrix (dECM) plays a vital role in controlling cell functions because of its similarity to the in vivo microenvironment. In the process of stem cell differentiation, the composition of the dECM is not constant but is dynamically remolded. However, there is little information regarding the dynamic regulation by the dECM of the osteogenic differentiation of stem cells. Herein, four types of stepwise dECMs (0, 7, 14, and 21 d-ECM) were prepared from bone marrow-derived mesenchymal stem cells (BMSCs) undergoing osteogenic differentiation for 0, 7, 14, and 21 days after decellularization. In vitro experiments were designed to study the regulation of BMSC osteogenesis by dECMs. The results showed that all the dECMs could support the activity and proliferation of BMSCs but had different effects on their osteogenic differentiation. The 14d-ECM promoted the osteogenesis of BMSCs significantly compared with the other dECMs. Proteomic analysis demonstrated that the composition of dECMs changed over time. The 14d ECM had higher amounts of collagen type IV alpha 2 chain (COL4A2) than the other dECMs. Furthermore, COL4A2 was obviously enriched in the activated focal adhesion kinase (FAK)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways. Thus, the 14d-ECM could promote the osteogenic differentiation of BMSCs, which might be related to the high content of COL4A2 in the 14d-ECM by activating the FAK/PI3K/AKT signaling pathways.

HNRNPA2B1, as a m6A Reader, Promotes Tumorigenesis and Metastasis of Oral Squamous Cell Carcinoma.

N6-methyladenosine (m6A) modification is the most prevalent modification on eukaryotic RNA, and the m6A modification regulators were involved in the progression of various cancers. However, the functions of m6A regulators in oral squamous cell carcinoma (OSCC) remain poorly understood. In this study, we demonstrated that 13 of 19 m6A-related genes in OSCC tissues are dysregulated, and HNRNPA2B1 was the most prognostically important locus of the 19 m6A regulatory genes in OSCC. Moreover, HNRNPA2B1 expression is elevated in OSCC, and a high level of HNRNPA2B1 is significantly associated with poor overall survival in OSCC patients. Functional studies, combined with further analysis of the correlation between the expression of HNRNPA2B1 and the EMT-related markers from the TCGA database, reveal that silencing HNRNPA2B1 suppresses the proliferation, migration, and invasion of OSCC via EMT. Collectively, our work shows that HNRNPA2B1 may have the potential to promote carcinogenesis of OSCC by targeting EMT via the LINE-1/TGF-ß1/Smad2/Slug signaling pathway and provide insight into the critical roles of HNRNPA2B1 in OSCC.

Biological information and functional analysis reveal the role of discoidin domain receptor 1 in oral squamous cell carcinoma.

OBJECTIVES: This study aimed to establish a framework for the role of discoidin domain receptor 1 (DDR1) in oral squamous cell carcinoma (OSCC) through biological data and functional analysis. STUDY DESIGN: The GSE31056 series of the Gene Expression Omnibus database and UALCAN website were used to assess DDR1 expression in head and neck squamous cell carcinoma (HNSCC) and OSCC. DDR1 RNA sequencing data for 260 HNSCC samples from The Cancer Genome Atlas were overlaid to evaluate its association with tumor progression and prognosis. To identify the function of DDR1 in OSCC, 38 patients with OSCC were followed for 8 years and immunohistochemical analysis, western blotting, Cell Counting Kit-8, and colony formation assays were conducted on OSCC cell lines to reveal DDR1 expression and function. RESULTS: DDR1 was overexpressed in HNSCC and OSCC tumor specimens and its expression correlated with overall survival and T-stage classification (P = .049, P = .0316). Furthermore, DDR1 was related to OSCC tumor growth because its expression increased with the T-stage level (P = .0071) but not N-stage level, histologic stage, or recurrence (P > .05). DDR1 was highly expressed in OSCC cell lines and promoted cell proliferation, which was repressed by nilotinib (P < .05). CONCLUSIONS: DDR1 has an oncogenic role in OSCC and might be a novel target for anti-OSCC therapy.

HoxB9 promotes the migration and invasion via TGF-ß1/Smad2/Slug signaling pathway in oral squamous cell carcinoma.

HoxB9, as a HOX family member, is known to play important roles in embryonic development. Recent studies have shown that HoxB9 is involved in cancer progression. However, little is known about the role of HoxB9 and the underlying mechanisms that suppress oral squamous cell carcinoma (OSCC) progression. In the present study, we used immunohistochemical staining to demonstrate that HoxB9 is over-expressed in OSCC cells and found that high levels of HoxB9 were significantly associated with shorter overall survival in patients with OSCC. Functional studies revealed that knocking down HoxB9 in OSCC cells using RNA interference decreased the migration and invasion of OSCC cells in vitro. Our mechanistic studies suggested that HoxB9 could stimulate the migration and invasion of OSCC cells by targeting EMT via the TGF-ß1/Smad2/Slug signaling pathway. Collectively, these findings suggest the vital roles of HoxB9 in OSCC progression through its effects in promoting EMT.

Inhibiting ROS-NF-κB-dependent autophagy enhanced brazilin-induced apoptosis in head and neck squamous cell carcinoma.

Autophagy modulation has been considered a potential therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). A previous study confirmed that brazilin might possess significant anti-carcinogenic activity. However, whether brazilin induces autophagy and its roles in cell death in HNSCC are still unclear. In this study, we have shown that brazilin induced significant apoptosis in the Cal27 HNSCC cell line but not in oral keratinocyte cell line (OKC). In addition to showing apoptosis induction, we demonstrated the brazilin-induced autophagic response in the Cal27 cells, as evidenced by the formation of GFP-LC3 puncta, and also showed the upregulation of LC3-II and Beclin-1. Moreover, pharmacologically or genetically blocking autophagy enhanced the brazilin-induced apoptosis, indicating the cytoprotective role of autophagy in brazilin-treated Cal27 cells. Moreover, brazilin activated nuclear factor kappa B (NF-κB p65) nuclear translocation and increased NF-κB p65 reporter activity, which contributed to the upregulation of autophagy-related genes, including LC3-II and Beclin-1. Importantly, we found that brazilin triggered reactive oxygen species (ROS) generation in Cal27 cells. Furthermore, N-acetyl-cysteine (NAC), a ROS scavenger, abrogated the effects of brazilin on the NF-κB p65-dependent autophagy. Taken together, our results demonstrated that brazilin increased the NF-κB p65-dependent autophagy through the promotion of ROS signalling pathways in HNSCC. These data also suggest that a strategy of blocking ROS-NF-κB p65-dependent autophagy to enhance the activity of brazilin warrants further attention for the treatment of HNSCC.