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Background: Oral squamous cell carcinoma (OSCC) is one of the most common malignancies. However, there is no effective treatment for OSCC., Purpose: This study aimed to identify a natural compound with significant efficacy against OSCC and elucidate its primary mechanism of action., Methods: An FDA-approved drug library and an MCE autophagy-related molecular compound library were screened through high-throughput screening to identify an effective natural compound against OSCC. The IC50 value of sanguinarine (Sang) in OSCC cells was determined using a CCK8 assay. Immunoblotting and immunofluorescence staining were used to assess the effect of Sang on autophagic flux in OSCC cells. Changes in the acidic lysosomal environment were evaluated using RFP-GFP-LC3B and LysoSensor Green DND-189. Furthermore, limited proteolysis-coupled mass spectrometry (LiP-MS) and virtual screening techniques were utilized to identify direct binding targets of Sang, which were subsequently validated by surface plasmon resonance (SPR) and microscale thermophoresis (MST). Molecular docking combined with molecular dynamics analysis identified the binding site between the target protein and Sang. In vitro and in vivo investigations with mutant plasmids confirmed this finding., Results: Screening led to the identification of the naturally occurring autophagy modulator Sang as a potent inhibitor of OSCC progression. Moreover, Sang impaired lysosomal function through reducing lysosomal-associated membrane proteins, inhibiting lysosomal proteolysis, and altering the lysosomal pH. These effects contributed to defects in autophagic clearance and subsequently suppressed OSCC progression. Notably, Sang bound the phenylalanine 26 (F26) residue in pyruvate kinase M2 (PKM2) and inhibited PKM2 enzymatic activity, subsequently suppressing transcription factor EB (TFEB) expression to inhibit lysosomal function and blocking autophagic flux in OSCC cells., Conclusion: Our results demonstrate for the first time that Sang can suppress the PKM2/TFEB axis, and influence lysosomal function, thereby blocking autophagy and inhibiting the progression of OSCC, making it a promising therapeutic option for the treatment of OSCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Purpose: To explore the effect of overexpression of DCN（decorin） gene on the expression of epidermal growth factor receptor (EGFR), cellular-myelocytomatosis viral oncogene (C-Myc) and cyclin dependent kinase inhibitor (p21)in tumor-bearing nude mice with oral squamous cell carcinoma（OSCC）., Methods: The expression of DCN gene in human oral squamous cell carcinoma(HSC-3) was up-regulated by liposome transfection. Nude mice were used as the carrier of OSCC. H-E staining was used to determine the pathological grade of tumor-bearing tissues in each group. Immunohistochemistry was used to detect the expression of EGFR, C-Myc and p21 protein in tumor-bearing tissues of each group after DCN overexpression. RT-qPCR and Western blot were used to quantitatively detect the expression of EGFR, C-Myc and p21 in tumor-bearing tissues of each group after DCN overexpression, and to determine the effects of DCN overexpression on the expression of EGFR, C-Myc and p21 in tumor-bearing tissues of OSCC nude mice. SPSS 20.0 software package was used for statistical analysis., Results: H-E staining showed that the animal model of OSCC was successfully constructed. The tumor-bearing tissues of nude mice in the plasmid group were significantly lighter than those in the empty vector group and non-transfected group(P＜0.05). IHC results showed that DCN, EGFR, C-Myc and p21 proteins were expressed in the tumor-bearing tissues of nude mice in each group, the expression of DCN,EGFR and C-Myc proteins in the plasmid group was significantly different from the other groups(P＜0.05).There was no significant differece in p21 protein expression in each group(P＞0.05). RT-qPCR and Western blot results showed that DCN, EGFR, C-Myc and p21 were expressed in diffrent degrees in tumor-bearing tissues of nude mice（P＜0.05）., Conclusions: DCN can inhibit the growth of tumor in OSCC nude mice. In tumor-bearing tissues of nude mice with OSCC, overexpression of DCN can down-regulate the expression of EGFR and C-Myc, and up-regulate the expression of p21.DCN may play an inhibitory role in the occurrence and development of OSCC.

Objectives/hypothesis: Human papilloma virus (HPV) infection has been confirmed as a favorable prognostic factor in oropharyngeal cancer. However, the prognostic value of HPV in oral squamous cell carcinoma (OSCC) is still unclear. Therefore, a systematic review and meta-analysis was performed to evaluate the prognostic value of HPV infection in OSCC patients., Study Design: Systematic literature review with meta-analysis., Methods: A systematic literature review was conducted in accordance with PRISMA guidelines in PubMed, EMBASE, and MEDLINE databases. The primary outcomes were overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and secondary outcomes were local control (LC), regional control (RC), and distant control (DC)., Results: A total of 22 articles with 3065 OSCC patients were included in this study. Meta-analysis demonstrated that compared to HPV-negative OSCC patients, HPV-positive OSCC patients had a significantly shorter OS (hazard ratio [HR] = 1.45, 95% confidence intervals [CI], 1.10-1.93) and lower DC (HR = 2.16, 95% CI, 1.54-3.04). There was no significant difference in DFS (HR = 1.20, 95% CI, 0.63-2.26), DSS (HR = 1.20, 95% CI, 0.63-2.26), LC (HR = 1.44, 95% CI, 0.97-2.14), and RC (HR = 1.50, 95% CI, 0.98-2.30) between HPV-positive and negative OSCC patients. Sensitivity analysis confirmed the above results., Conclusions: Our systematic review and meta-analysis reveal that HPV-positive is associated with significantly decreased OS and DC, suggesting HPV infection is an adverse prognostic factor in OSCC. Laryngoscope, 132:1760-1770, 2022., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

Gene fusion is caused by the linkage of previously separate genes or sequences. Recently, an increasing number of novel fusion genes have been identified and associated with tumor progression, and several of them have been suggested as promising targets for tumor therapy. However, there are hardly any studies reporting the association of fusion genes with the progression of oral squamous cell carcinoma (OSCC). In this study, we identified a total of 11 fused genes in OSCC cells. We further analyzed the structure of one fused gene, TRIM52-RACK1, and detected its function in tumor progression in vitro. We found that TRIM52-RACK1 was caused by a deletion of 181,257,187-181,247,386 at 5q35.3 and it promoted OSCC cell proliferation, migration, and invasion. Therefore, TRIM52-RACK1 can be a promising target for tumor therapy in OSCC., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020. Published by Elsevier Ltd.)

Oral squamous cell carcinoma (OSCC), with high potential for metastasis, is the most common malignant tumor of the head and neck. Cancer‑associated fibroblasts (CAFs) are the main stromal cells in the microenvironment and aggravate tumor progression. However, whether CAFs are associated with the progression of OSCC remains unknown and the underlying mechanism remains unclear. In the present study, the role of CAFs in mediating OSCC cell migration and invasion was investigated, and the participation of exosomal miR‑382‑5p in this process was elucidated. In this study, according to the α‑SMA staining with immunohistochemistry, 47 OSCC patients were divided into CAFs‑rich and CAFs poor groups, and association of CAF density and clinicopathologic features of the OSCC patients were analyzed with Pearson χ2 test. Transwell assay was used for evaluating cell migration and invasion ability of OSCC cells after being co‑cultured with NFs or CAFs, or after added exosomes. qPCR was used to detect the expression of miR‑382‑5p. Western blot analysis was used to measure the expression of migration and invasion‑associated proteins. In the present study, the CAF density in tumor tissues was found to be relevant to OSCC lymph node metastasis and TNM stage. Furthermore, we revealed that miR‑382‑5p was overexpressed in CAFs compared with that in fibroblasts of adjacent normal tissue and miR‑382‑5p overexpression was responsible for OSCC cell migration and invasion. Finally, we demonstrated that CAF‑derived exosomes transported miR‑382‑5p to OSCC cells. The present study confirmed a new mechanism of CAF‑facilitated OSCC progression and may be beneficial for identifying new cancer therapeutic targets.

Lymph node ratio (LNR) has been shown to be an independent prognostic factor for oral squamous cell carcinoma (OSCC) in various centre-based studies recently. A range of cut-off values have been suggested. A meta-analysis was performed to evaluate the prognostic effects of LNR and to investigate the cut-off value. Electronic search on Pubmed, Embase and Cochrane library and manual search were performed for studies up to January 2018. The outcomes were overall survival (OS), disease specific survival (DSS), disease free survival (DFS), local recurrence free survival (LF), locoregional disease free survival (LRF), and distant metastasis disease free survival (DM). 19 studies between 2009 and 2017 were included. The total number of patients was 14,254 (range 19-3958). Data was grouped into Group A (with pathological nodal disease, pN+) and Group B (with and without pathological nodal disease, pN+ and pN-). In the meta-analysis, the high LNR was significantly related to short OS (A = HR 1.902; 95%CI: 1.453-2.488, B = HR 2.76; 95%CI: 2.13-3.59), DSS (A = HR 1.728; 95%CI: 1.159-2.579; B = HR 2.83; 95%CI: 1.8-4.44) and DFS (A = HR 2.27; 95%CI: 1.74-2.96; B = HR 2.01; 95%CI: 1.44-2.82) in both groups; and shorter LRF in Group B (HR 5.013; 95%CI: 3.584-7.011). In the analysis, all cut-off values were shown to be significant and there was no strong evidence to consider a possibility of a second significant value. Based on our results, LNR is an independent prognostic factor in OSCC and may be considered in future oncologic staging systems., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Radiotherapy is one of the most effective non-surgical treatments for oral squamous cell carcinoma. However, radioresistance remains a major impediment to radiotherapy. Although BetA (Betulinic acid) can induce radiosensitization, the underlying mechanism and whether it could induce radiosensitization in oral squamous cell carcinoma are not fully understood. In this study, we showed that BetA increased radiosensitization in CAL-27 and Tca-83 cells. Radiation-triggered Sp1 overexpression was responsible for radioresistance of OSCC (oral squamous cell carcinoma) cells. Treatment with BetA downregulated Sp1 and upregulated PTEN through inducing Sp1 sumoylation and correspondingly increased radiosensitization. Moreover, Sumoylation of Sp1 upregulated PTEN protein expression by downregulating Sp1 as well as inhibiting Sp1 DNA binding activity, thereby leading to the activation of PTEN transcription. Our results suggested that BetA was able to enhance radiosensitization at least partially by downregulating Sp1 and upregulating PTEN through inducing Sp1 sumoylation. BetA is suggested to be a promising drug for increasing radiosensitization in oral squamous cell carcinoma radiotherapy.

Unlabelled: Induction chemotherapy (ICT) is a controversial treatment for head and neck squamous cell carcinomas (HNSCC). Despite numerous randomized controlled trials (RCTs), a majority do not have enough statistical power alone to conclude ICT's treatment value among oral squamous carcinoma patients (OSCC) since many addressed HNSCC as one entity instead of by specific subtypes. By performing a systematic review and cumulative meta-analysis, we aim to determine the benefits of ICT in OSCC therapy. A literature search identified for RCTs comparing OSCC patients who received ICT against those without. Log-hazard ratio, and relative risk were used for comparison. Heterogeneity was determined using the I(2) statistic package. The primary endpoint was overall survival (OS), followed by disease-free survival (DFS), locoregional recurrence (LRR) and distant metastasis (DM) as secondary endpoints., Results: 27 randomized trials were included for analysis (n=2872 patients). The shortest median follow-up was 15months whereas the longest was 11.5years. ICT does not improve OS (HR=0.947, 95% CI 0.85-1.05, p=0.318), DFS (RR=1.05, 95% CI 0.92-1.21, p=0.462) and DM (RR=0.626, CI 95% 0.361-1.086, p=0.096) compared to locoregional treatment alone. However, there was a significant improvement to LRR (RR=0.778, 95% CI 0.622-0.972, p=0.027). There is no evidence ICT improves survival outcomes for OSCC patients. However, ICT reduces locoregional recurrence of OSCC, which may need further verification., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Oral squamous cell carcinoma (OSCC) is a frequently diagnosed life-threatening oral cancer worldwide and has become one of the leading causes of cancer-related mortality. However, the pathogenesis of this disease is very limited., Objective: In this study, we aimed to investigate the functional relationship between OSCC and a potential tumor related gene ubiquitin-specific proteases 39 (USP39)., Methods: The lentivirus-based RNA interference was utilized to knock down USP39 expression in human OSCC CAL27 cells. The effect of USP39 on cell proliferation was detected by MTT and colony formation assays., Results: The results uncovered that the proliferation rate was significantly decreased in specific USP39-targeting lentivirus infected cells compared to control lentivirus infected cells. The colony formation capacity was also attenuated in CAL27 cells after USP39 knockdown. Moreover, knockdown of USP39 arrested CAL27 cells in S and G1/M phases of the cell cycle. Furthermore, USP39 silencing induced apoptosis of CAL27 cells via activations of Caspase 3 and PARP., Conclusions: In conclusion, the inhibition of USP39 in CAL27 cells suppressed cell growth probably via induction cell cycle arrest and apoptosis. USP39 might act as an oncogenic factor in OSCC and could be a potential molecular target for OSCC gene therapy.

There has been little research conducted regarding autophagy in oral squamous cell carcinoma (OSCC). Given the prevalence of oral cancers which are OSCC and the severe side effects of current treatments, there is a pressing need to develop effective alternative therapies. In this study, we have endeavored to explore the biological characteristics of oral squamous cell carcinoma cell line KB cells, in particular with regard to the role played by autophagy in their survival. Autophagy was activated by nutrient depletion via culturing cells in Earle's balanced salts (EBSS) and was measured via indices relating to Beclin 1, microtubule-associated protein light chain 3 (MAPLC3, LC3), p62, and Green fluorescent protein-light chain 3 plasmid transfection (GFP-LC3). Cell death and apoptosis induced by nutrient depletion was measured using both MTT assay and flow cytometry (FCM). Compared to initial levels at 0 h, Beclin 1 density in EBSS-treated cells was found to have increased at 6, 12, and 18 h in a time-dependent manner and was found to have subsequently declined at 24 and 48 h. p62 levels, LC3-II/LC3-I ratio, and GFP-LC3 levels increased at 6, 12, 18, 24, and 48 h in a time-dependent manner. 3-methyladenine (3-MA) was found to inhibit autophagy and the expression of Beclin 1 and significantly enhanced nutrient depletion-induced apoptosis and death. We concluded that nutrient depletion enhances OSCC cell autophagy in time-course patterns and that the inhibition of autophagy augments apoptosis in OSCC cells. We also deduced that Beclin 1 takes part in the development and progression of autophagy, potentially playing an important role in the crosstalk between apoptosis and autophagy in OSCC cells. These findings suggest that nutrient depletion may be an effective way to explore autophagy and that autophagy inhibitors should be investigated as a potential novel agent for the adjuvant treatment of human OSCC., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)