Oral Cancer Incidence, Mortality, and Mortality-to-Incidence Ratio Are Associated with Human Development Index in China, 1990-2019.

The burden of oral cancer (OC) is closely related to economic development. We aimed to evaluate the burden of OC at different stages of economic development in China in terms of incidence, mortality, and mortality-to-incidence ratio (MIR) from 1990 to 2019. Data on cancer in China from 1990 to 2019 were obtained from the Global Burden of Disease 2019. Based on human development index (HDI), Chinese economic development was divided into three stages: low, medium, and high HDI stages. Mann-Whitney U-test was used to evaluate the differences in age-standardised incidence rates (ASIR), age-standardised mortality rates (ASMR), and MIR at various stages of HDI. Correlation and regression tests were conducted to examine the association amongst ASIR, ASMR, MIR, and HDI in OC. The estimated annual percentage changes (EAPCs) were calculated to assess the trend of ASIR, ASMR, and MIR. Significant differences were observed in terms of ASIR, ASMR, and MIR between groups (P < 0.001). The values of both sexes in the low HDI stage were lower than those of the medium and high HDI stages, except for MIR, in which the low HDI stage was the highest (P < 0.05). ASIR and ASMR of OC in males at the medium HDI stage showed the fastest growth rate with EAPC values of 5.64 (95% confidence interval, 95% CI, 5.20 to 6.08) and 4.42 (95% CI, 4.01 to 4.82), respectively. A strong positive correlation exists between HDI and ASIR (r = 0.96) and ASMR (r = 0.91) in both sexes from 1990 to 2019. During the high HDI stage, the ASIR and ASMR of OC were at a high level, but the ASIR halted the uptrend trend and ASMR showed a decreasing trend. Therefore, the HDI index has been positively correlated with the ASIR and ASMR of OC in China in the past 30 years, but this relationship may not be sustained as the economy develops. The health department should continue to allocate additional resources for the prevention and treatment of OC.

Burden of Oral Cancer on the 10 Most Populous Countries from 1990 to 2019: Estimates from the Global Burden of Disease Study 2019.

BACKGROUND: Oral cancer (OC) is a common tumour that poses a threat to human health and imposes a heavy burden on countries. This study assessed the burden imposed by OC on the 10 most populous countries from 1990 to 2019 on the basis of gender, age and socio-demographic index. METHODS: Data on incidence, mortality, disability-adjusted life years (DALY) and corresponding age-standardised rates (ASR) for OC in the 10 most populous countries from 1990 to 2019 were derived from the Global Burden of Disease Study 2019. Estimated annual percentage changes were calculated to assess the trends of morbidity, mortality and DALY. The indicator that served as a proxy for survival rate was the supplement of mortality-to-incidence ratio (SMIR) (1 - (M/I)). RESULTS: The number of new cases, deaths and DALY have increased in all 10 countries in the past 30 years. Trends in age-standardised incidence rates (ASIR), age-standardised mortality rate (ASMR) and age-standardised DALY for OC in the 10 most populous countries varied. The SMIR increased in all countries, with most countries having an SMIR between 30% and 50%. In 2019, the United States had the highest SMIR at 76%, whereas Russia had the lowest at 21.7%. Incidence and mortality were close between male and female subjects in Japan, Indonesia, Mexico, India, Bangladesh and Pakistan. The incidence and mortality in male subjects in the United States, Russia, China and Brazil were two or more times those of female subjects. Gender difference was highest among patients aged 40-69 years. CONCLUSION: Trends and gender differences in ASIR, ASMR and age-standardised DALY for OC vary in the 10 most populous countries. Government cancer programs are often expensive to run, especially in countries with large populations. Policy makers need to take these differences into account when formulating policies.

Research Achievements of Oral Submucous Fibrosis: Progress and Prospect.

Oral submucous fibrosis (OSMF) is a kind of chronic, insidious disease, and it is categorized into potentially malignant disorders (PMD), which poses a global and regional problem to public health. It is considered to be a multifactorial disease, such as due to areca nut chewing, trace element disorders, and genetic susceptibility. However, there is still no unanimous conclusion on its pathogenesis, diagnosis, and treatment strategies. Hence, this article provides a comprehensive review and prospect of OSMF research, providing scholars and clinicians with a better perspective and new ideas for the research and treatment of OSMF.

Preemptive Oral Etoricoxib on Health-Related Quality of Life after Mandibular Third Molar Surgery: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

This study was aimed at evaluating the use of oral etoricoxib for preemptive analgesia on the health-related quality of life (QoL) outcome after the extraction of mandibular third molar. The study population consisted of 60 participants that required extraction of a single partial bony impacted mandibular third molar under local anesthesia and met the inclusion criteria. The participants were randomized into two groups. The etoricoxib group orally received 60 mg etoricoxib 30 min before surgery, whereas the control group was given a placebo. The patients were assessed postoperatively after 1, 2, 3, 4, 5, 6, and 7 days using the United Kingdom oral health-related QoL questionnaire and visual analog scale for maximum postoperative pain. The total dose of ibuprofen rescue intake and total number of days the drug was taken were recorded. Surgical removal of impacted teeth had a negative influence on the patient's QoL across various physical, social, and psychological aspects. The scores for postoperative pain in the etoricoxib group were significantly lower than those in the control group on each postoperative observation day. The number of patients without analgesic rescue medication, the average amount, and total number of days emergency analgesics were taken were significantly lower in the etoricoxib group than in the control group. The etoricoxib group showed better QoL score than the control group. Preemptive oral etoricoxib is an effective therapeutic strategy for improving the QoL after surgical removal of the impacted lower third molar.

[Multidisciplinary team model for patients with oral cancer and systemic diseases: an expert consensus].

Large general hospitals currently play an increasingly important role in the diagnosis and treatment for acute critical patients and difficult diseases because of the development of dual referral system and hierarchical diagnosis, as well as the formation of medical treatment alliance. Patients with oral cancers are often associated with systemic diseases, which increases the complexity of the condition. Thus, meeting the demand through the traditional single medical model is difficult. As such, a multidisciplinary team (MDT) model has been proposed and has achieved a good clinical effect. To standardize the application of this model, we organized an event in which relevant experts discussed and formulated a consensus to provide standardized suggestions on the MDT process and the diagnosis and treatment of common systemic diseases as reference for clinical practice.

[Relationship among areca nut, intracellular reactive oxygen species, and autophagy].

The relationship between areca nut as a primary carcinogen and oral cancer has been widely concerned. Areca can change the levels of reactive oxygen species (ROS) and autophagy in cells, and the levels of ROS and autophagy are closely related to the occurrence and development of tumors. This paper reviewed the relationships among areca nut, intracellular ROS, and autophagy.

Application of Delayed Surgical Managements in Patients with Stensen's Duct Injury.

The study aimed to retrospectively evaluate surgical treatment outcomes after delayed parotid gland and duct injuries. Nine patients subjected to parotid gland and duct injuries with 1- to 3-month treatment delay were retrospectively evaluated with special reference of etiology, past medical history, and injury location. Conservative treatment, microsurgical anastomosis, and diversion of salivary flow or ligation were chosen for delayed parotid gland and duct injuries concerning to their site of injury, time of repair and procedures. Assistant treatment as pressure dressing was adopted thereafter. All patients experienced an uneventful recovery at the time of finalizing the study. Two patients received Stensen's duct ligation, 5 received microsurgical anastomosis and 2 accepted salivary flow diversion for 5 patients with sialoceles and 4 patients with fistulas, and no re-occurrence was found. Facial paralysis occurred after surgery in 4 patients, and 3 of them recovered after the nerve nutrition treatment. Our study suggested that appropriate surgical treatment is efficient for the re-establishment of the tissue function and facial aesthetic for delayed injury of the parotid and its duct.

Hypoxia Enhances Fusion of Oral Squamous Carcinoma Cells and Epithelial Cells Partly via the Epithelial-Mesenchymal Transition of Epithelial Cells.

Increasing evidence and indications showed that cell fusion is crucial in tumor development and metastasis, and hypoxia, a closely linked factor to tumor microenvironment, which can lead to EMT, induces angiogenesis and metastasis in tumor growth. However, the relationship between hypoxia and fusion has not been reported yet. EMT will change some proteins in the epithelial cell surface and the changes of proteins in cell surface may increase cell fusion. This study found that hypoxia promotes the spontaneous cell fusion between Oral Squamous Carcinoma Cells (OSCCs) and Human Immortalized Oral Epithelial Cells (HIOECs). At the same time, Hypoxia can lead to EMT, and hypoxia-pretreated HIOECs increased fusion rate with OSCC, while the fusion rate was significantly reduced by DAPT, a kind of EMT blocker. Therefore, epithelial cells can increase spontaneously cell fusion with OSCC by EMT. Our study may provide a new insight to link among tumor microenvironment, cell fusion, and cancer.

Autophagy Induced by Areca Nut Extract Contributes to Decreasing Cisplatin Toxicity in Oral Squamous Cell Carcinoma Cells: Roles of Reactive Oxygen Species/AMPK Signaling.

Chewing areca nut is closely associated with oral squamous cell carcinoma (OSCC). The current study aimed to investigate potential associations between areca nut extract (ANE) and cisplatin toxicity in OSCC cells. OSCC cells (Cal-27 and Scc-9) viability and apoptosis were analyzed after treatment with ANE and/or cisplatin. The expressions of proteins associated with autophagy and the AMP-activated protein kinase (AMPK) signaling network were evaluated. We revealed that advanced OSCC patients with areca nut chewing habits presented higher LC3 expression and poorer prognosis. Reactive oxygen species (ROS)-mediated autophagy was induced after pro-longed treatment of ANE (six days, 3 µg). Cisplatin toxicity (IC50, 48 h) was decreased in OSCC cells after ANE treatment (six days, 3 µg). Cisplatin toxicity could be enhanced by reversed autophagy by pretreatment of 3-methyladenine (3-MA), N-acetyl-l-cysteine (NAC), or Compound C. Cleaved-Poly-(ADP-ribose) polymerase (cl-PARP) and cleaved-caspase 3 (cl-caspase 3) were downregulated in ANE-treated OSCC cells in the presence of cisplatin, which was also reversed by NAC and Compound C. Collectively, ANE could decrease cisplatin toxicity of OSCC by inducing autophagy, which involves the ROS and AMPK/mTOR signaling pathway.

Up-regulation of syncytin-1 contributes to TNF-α-enhanced fusion between OSCC and HUVECs partly via Wnt/ß-catenin-dependent pathway.

Accumulating evidence implies that cell fusion is one of the driving forces of cancer invasion and metastasis. However, considerably less is still known about the triggering factors and underlying mechanisms associated with cancer-host cell fusion, particularly in inflammatory tumor microenvironment. In this study, we confirmed that inflammatory factor TNF-α could enhance fusion between squamous cell carcinoma cells 9 (SCC-9) and human umbilical vein endothelial cells (HUVEC). Further study revealed that TNF-α could promote up-regulation of syncytin-1 in SCC-9 and its receptor neutral amino acid transporter type 2 (ASCT-2) in HUVEC. Syncytin-1 acted as an important downstream effector in TNF-α-enhanced cancer-endothelial cell fusion. TNF-α treatment also led to the activation of Wnt/ß-catenin signal pathway in SCC-9. The activation of Wnt/ß-catenin signal pathway was closely associated with the up-regulation of syncytin-1 in SCC-9 and increased fusion between SCC-9 and HUVEC while blocking of Wnt/ß-catenin signal pathway resulted in the corresponding down-regulation of syncytin-1 accompanied by sharp decrease of cancer-endothelial cell fusion. Taking together, our results suggest that Wnt/ß-catenin signal pathway activation-dependent up-regulation of syncytin-1 contributes to the pro-inflammatory factor TNF-α-enhanced fusion between oral squamous cell carcinoma cells and endothelial cells.

EphA2 silencing promotes growth, migration, and metastasis in salivary adenoid cystic carcinoma: in vitro and in vivo study.

EphA2 is associated with tumor growth and distant metastasis in numerous human tumors. Considering the controversial effects of EphA2 in different tumors and the lack of reports in salivary adenoid cystic carcinoma (SACC), we evaluated the effects of EphA2 inhibition by short hairpin RNA on SACC through in vivo and in vitro researches for the first time. Real-time reverse transcriptase-PCR and western blot analysis were conducted to verify the interference effect on SACC cells. Using Cell Counting Kit-8, wound healing, Transwell and Matrigel adhesion assays, we confirm that inhibition of EphA2 promotes the migration, invasion and adhesion ability of SACC cells. In vivo research, we prove that silencing of EphA2 significantly accelerates tumor growth and lung metastasis ability by establishing xenograft models in mice, including subcutaneous inoculation and tail vein injection. In addition, immunostaining of EphA2, E-cadherin and Slug from 40 specimens and in vitro simulation of perineural invasion (PNI) assay imply that suppression of EphA2 partially contribute to epithelial-mesenchymal transition and enhancement of PNI in SACC. In conclusion, all the data suggest that EphA2 may act as a tumor suppressor in SACC progression.

Membrane microvesicles as mediators for melanoma-fibroblasts communication: roles of the VCAM-1/VLA-4 axis and the ERK1/2 signal pathway.

Recent studies suggest that microvesicles (MVs) within the tumor microenvironment are emerging as potent mediators for cell-cell communication. In this study, we investigated the MV-mediated transformation of normal fibroblasts to tumor-associated fibroblasts, focusing on the functional regulation of vascular cell adhesion molecule-1 (VCAM-1) expression. After incubation with melanoma-derived MVs, the fibroblasts (NIH/3T3 cells) presented an obvious enhancement of VCAM-1 expression in an ERK1/2-activation-dependent manner, and this enhancement was further increased when the MVs were from highly metastatic melanoma cells. The adhesion analysis showed that the VCAM-1/VLA-4 axis is involved in the preferential attachment of highly metastatic melanoma cells and BMSCs to MV-educated fibroblasts. Hypoxia promoted melanoma-fibroblast interaction by directly upregulating VLA-4 expression in highly metastatic melanoma cells and indirectly provoking VCAM-1 expression in fibroblast cells via melanoma-released MVs. Moreover, MV-educated fibroblasts increased IL-6, fibroblast activation protein and EGF expression simultaneously. Proteomic analysis of MVs suggested that numerous signal pathways in addition to the MAPK signal pathway are regulated by melanoma MVs, which function as tumor messengers that participate in melanoma progression.

Oral cancer/endothelial cell fusion experiences nuclear fusion and acquisition of enhanced survival potential.

Most previous studies have linked cancer-macrophage fusion with tumor progression and metastasis. However, the characteristics of hybrid cells derived from oral cancer and endothelial cells and their involvement in cancer remained unknown. Double-immunofluorescent staining and fluorescent in situ hybridization (FISH) were performed to confirm spontaneous cell fusion between eGFP-labeled human umbilical vein endothelial cells (HUVECs) and RFP-labeled SCC9, and to detect the expression of vementin and cytokeratin 18 in the hybrids. The property of chemo-resistance of such hybrids was examined by TUNEL assay. The hybrid cells in xenografted tumor were identified by FISH and GFP/RFP dual-immunofluoresence staining. We showed that SCC9 cells spontaneously fused with cocultured endothelial cells, and the resultant hybrid cells maintained the division and proliferation activity after re-plating and thawing. Such hybrids expressed markers of both parental cells and became more resistant to chemotherapeutic drug cisplatin as compared to the parental SCC9 cells. Our in vivo data indicated that the hybrid cells contributed to tumor composition by using of immunostaining and FISH analysis, even though the hybrid cells and SCC9 cells were mixed with 1:10,000, according to the FACS data. Our study suggested that the fusion events between oral cancer and endothelial cells undergo nuclear fusion and acquire a new property of drug resistance and consequently enhanced survival potential. These experimental findings provide further supportive evidence for the theory that cell fusion is involved in cancer progression.

Correlation of deregulated like-acetylglucosaminyl transferase and aberrant α-dystroglycan expression with human tongue cancer metastasis.

PURPOSE: The present study examined the correlation of α-dystroglycan (α-DG) expression and like-acetylglucosaminyl transferase (LARGE) with metastasis of human tongue cancer. MATERIALS AND METHODS: Fifty human tongue cancer tissues and 2 tongue squamous cell carcinoma cell lines (CAL27 and SCC4) were involved. Immunohistochemistry was used to detect the expression of α-DG and LARGE. Methylation-specific polymerase chain reaction was performed to assess the methylation status of the LARGE gene promoter. CAL27 and SCC4 cells were transfected with exogenous LARGE and treated with 5-aza-2'-deoxycytidine (Aza-dC), respectively. Glycol sites of α-DG were detected by western blotting. In addition, the laminin overlay assay, cell adhesion assay, and invasion assay were performed. RESULTS: Immunohistochemical results showed that decreased expression of VIA4-1 and IIH6 (antibodies that recognize the glycol sites of α-DG) were correlated with the lymph node metastasis of tongue cancer (n = 50; P = .016 and .025, respectively). Decreased LARGE expression and hypermethylation of the LARGE gene promoter were correlated with lymph node metastasis and α-DG glycosylation in human tongue cancer (n = 50; P = .043 and .015 respectively). In addition, LARGE overexpression and Aza-dC treatment actively led to restoration of functional α-DG expression, elevation of laminin binding, and decrease of migratory ability in cancer cells. CONCLUSION: The results suggested that absent α-DG expression and LARGE deregulation were closely associated with nodal metastasis of tongue cancer. Aberrant α-DG expression and glycosylation were attributed at least in part to the abnormal epigenetic modification of LARGE, especially the hypermethylation of its promoter.

Alterations of high endothelial venules in primary and metastatic tumors are correlated with lymph node metastasis of oral and pharyngeal carcinoma.

High endothelial venules (HEVs) are special blood vessels in the paracortical region of lymph nodes (LNs) and govern lymphocyte recruitment. LN metastasis has similarity to circulating lymphocytes homing to LNs, but the role of HEVs in the progression of oral and pharyngeal squamous cell carcinoma (OPSCC) is unclear. In this study, we found that HEVs experienced a series of morphological and functional changes during OPSCC progression and were correlated with LN metastasis. In 9 cases of 73 metastatic LNs, tumor emboli were located adjacent to HEVs or just out of the vessels but not lymphatic channels. Gap junctions of tumor cells close to HEVs decreased or disappeared, and gaps were left at contact points where tumor cells attached to the HEVs. Moreover, the proliferation rate of endothelial cells of HEVs was the highest in metastatic LNs. Finally, L-selectin was detected in both primary and metastatic tumors, and it facilitated tumor cells adhering to LNs. In conclusion, our findings suggest that remodeled HEVs are correlated with LN metastasis of OPSCC and play important role in this process by preparing premetastatic soil for cancer cell metastasis.

Ephrin-A1 is up-regulated by hypoxia in cancer cells and promotes angiogenesis of HUVECs through a coordinated cross-talk with eNOS.

Hypoxia, ephrin-A1 and endothelial nitric oxide synthase (eNOS) have been proved to play critical roles in tumor angiogenesis. However, how ephrin-A1 is regulated by hypoxia and whether ephrin-A1 cooperates with eNOS in modulation of angiogenesis remain to be addressed in details. Here we demonstrated that both ephrin-A1 in squamous cell carcinoma cells (SCC-9) and especially soluble ephrin-A1 in the supernatants were up-regulated under hypoxic condition. An increased nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) was observed in ephrin-A1-induced angiogenesis which was reversed after co-culture with eNOS specific inhibitor, N-nitro-L-arginine methyl ester hydrochloride (L-NAME). Western blot analysis confirmed that both phosphorylation of Akt(Ser473) and eNOS(Ser1177) were up-regulated in ephrin-A1-stimulated HUVECs, with the total eNOS expression unchanged. The specific inhibitor of phosphatidylinositol 3-kinase (PI3K), LY294002, significantly down-regulated ephrin-A1-induced expression of phosphorylated Akt(Ser473) as well as phosphorylation of eNOS(Ser1177). These results revealed a possible novel mechanism whereby ephrin-A1 is regulated in tumor microenvironment and promotes angiogenesis through a coordinated cross-talk with PI3K/Akt-dependent eNOS activation which may relate to normal vascular development and tumor neovascularization.

[Experimental study on ectopic prefabrication of vascularized mandible graft with autogenous ribs].

OBJECTIVE: To explore a method for ectopic prefabrication of mandible with vascular pedicle. METHODS: Cancellous bone blocks harvested from the dog ribs were packaged with mandible-shaped titanium mesh scaffold and implanted into latissimus dorsi of dog with thoracodorsal artery and vein through the scaffold. After 12 weeks, bone formation and vascularization were evaluated by gross inspection, histological examination and immunohistochemistry. RESULTS: Vascularized mandible with thoracodorsal artery and vein were formed and histological staining and immunohistochemisty confirmed new bone formation and vascularization. CONCLUSIONS: There is feasibility for ectopic prefabrication of vascularized mandible graft using cancellous ribs, which provides a new method for mandibular defect reconstruction. Experimental study on ectopic prefabrication of vascularized mandible graft with autogenous ribs.

Tumor necrosis factor-α enhanced fusions between oral squamous cell carcinoma cells and endothelial cells via VCAM-1/VLA-4 pathway.

Fusion between cancer cells and host cells, including endothelial cells, may strongly modulate the biological behavior of tumors. However, no one is sure about the driving factors and underlying mechanism involved in such fusion. We hypothesized in this study that inflammation, one of the main characteristics in tumor microenvironment, serves as a prominent catalyst for fusion events. Our results showed that oral cancer cells can fuse spontaneously with endothelial cells in co-culture and inflammatory cytokine tumor necrosis factor-α (TNF-α) increased fusion of human umbilical vein endothelium cells and oral cancer cells by up to 3-fold in vitro. Additionally, human oral squamous cell carcinoma cell lines and 35 out of 50 (70%) oral squamous carcinoma specimens express VLA-4, an integrin, previously implicated in fusions between human peripheral blood CD34-positive cells and murine cardiomyocytes. Expression of VCAM-1, a ligand for VLA-4, was evident on vascular endothelium of oral squamous cell carcinoma. Moreover, immunocytochemistry and flow cytometry analysis revealed that expression of VCAM-1 increased obviously in TNF-α-stimulated endothelial cells. Anti-VLA-4 or anti-VCAM-1 treatment can decrease significantly cancer-endothelial adhesion and block such fusion. Collectively, our results suggested that TNF-α could enhance cancer-endothelial cell adhesion and fusion through VCAM-1/VLA-4 pathway. This study provides insights into regulatory mechanism of cancer-endothelial cell fusion, and has important implications for the development of novel therapeutic strategies for prevention of metastasis.