UNASSIGNED: Tongue squamous cell carcinoma (TSCC) is a prevalent tumor that affects many people worldwide. Radiotherapy is a common treatment option, but its efficacy varies greatly. This study seeks to validate the identified gene signature associated with radiosensitivity in TSCC, and its potential in predicting radiotherapy response and prognosis.
UNASSIGNED: We analyzed 122 TSCC patients from TCGA database using the radiosensitivity signature and classified them into radiosensitive (RS) and radioresistant (RR) groups. Immune infiltration analysis methods were applied to investigate the immune status between different subgroups. Immunophenotype Score (IPS) and pRRophetic algorithm were employed to estimate the efficiency of treatment. A radioresistant TSCC cell line was established by gradually increasing radiation doses. Cell radiosensitivity was evaluated using the CCK-8 and colony formation assays. The expression of radiosensitivity-related genes was validated by qRT-PCR.
UNASSIGNED: Our study validated the predictive capacity of a previously identified \"31-gene signature\" in the TCGA-TSCC cohort, which effectively stratified patients into RS and RR groups. We observed that the RS group exhibited superior overall survival and progression-free survival rates relative to the RR group when treated with radiotherapy. The RS group was significantly enriched in most immune-related hallmark pathways, and may therefore benefit from immune checkpoint inhibitors. However, the RS group displayed lower sensitivity to first-line chemotherapy. A radioresistant TSCC cell line (CAL-27R) exhibited increased clonogenic potential and cell viability following irradiation, accompanied by downregulation of three radiosensitivity-related genes compared to its parental non-resistant cell (CAL-27). In addition, we constructed and validated a radiosensitivity-related prognostic index (PI) using 4 radiosensitivity-related genes associated with TSCC prognosis.
UNASSIGNED: We assessed the ability of the radiosensitivity gene signature to predict outcomes in TSCC patients. our research provided valuable insights into the molecular pathways associated with radiosensitivity in TSCC and offered clinicians a practical tool to predict patient radiotherapy effectiveness and prognosis.

Tongue squamous cell carcinoma (TSCC) is one of the most common malignant tumors among oral cancers, and its treatment is based on radio-chemotherapy and surgery, which always produces more serious side effects and sequelae. Traditional medicine can compensate for the shortcomings of modern medical treatments and play a better therapeutic role. Currently, active ingredients derived from plants are attracting the attention of researchers and clinical professionals. We examined capsaicin (CAP), an active ingredient isolated from Capsicum annuum (family Solanaceae), and explored the effect of CAP combined with cisplatin (DDP) on epithelial-mesenchymal transition (EMT) and TSCC cells migration. Our results demonstrated that Transforming growth factor-β1(TGF-β1) induced EMT and promoted cell migration in TSCC cells. CAP combined with DDP inhibits non-TGF-β1-induced or TGF-β1-induced EMT and migration. Mechanistically, the inhibition of non-TGF-β1-induced EMT and migration by CAP combined with DDP was mediated by the AMPK/mTOR pathway, whereas TGF-β1-induced EMT and migration were regulated by the Claudin-1/PI3K/AKT/mTOR pathway. A nude lung metastasis mouse model was established for in vivo validation. These results support our hypothesis that the combination of CAP and DDP inhibits TSCC metastasis. These data set the stage for further studies aimed at validating CAP as an effective active ingredient for enhancing chemotherapy efficacy and reducing the dosage and toxicity of chemotherapeutic drugs, ultimately paving the way for translational research and clinical trials for TSCC eradication.

OBJECTIVE: Integrin β5 (ITGB5) is an integrin β subunit member widely expressed in the human bodies, especially in cancer cells and tissues, which is a key factor in promoting tumor metastasis. In this study we investigated the differential expression of ITGB5 in tongue squamous cell carcinoma (TSCC), especially in those with lymph node metastasis, and revealed the possible mechanism.
METHODS: The expression of ITGB5 in TSCC was analyzed by database and verified by immunohistochemistry through 135 TSCC patients\' tissue sections from Sun Yat-sen Memorial Hospital and Guangzhou First People\'s Hospital. The relationship between ITGB5 and lymph node metastasis or prognosis was analyzed retrospectively. The effects of ITGB5 on TSCC cells were examined through knocking down or overexpression and its possible regulator and signal pathway were explored.
RESULTS: The expression of ITGB5 in TSCC was higher than that in adjacent tissue, and the expression in patients with lymph node metastasis was higher than that in patients without lymph node metastasis. The high expression of ITGB5 predicted a worse prognosis. Knock down of ITGB5 suppressed invasion and migration of TSCC cells, while overexpression of ITGB5 contributed to invasion and migration. Reactive oxygen species (ROS) regulated epithelial mesenchymal transition (EMT), and we further verified that ROS enhanced the expression of ITGB5 to promote the metastasis of TSCC. Mechanistically, ITGB5 functions through cell adhesion signal pathway.
CONCLUSIONS: The increased expression of ITGB5 in tongue squamous cell carcinoma with lymph node metastasis may be a potential target for evaluating lymph node metastasis and worse prognosis of tongue squamous cell carcinoma. Scavenge of ROS or knock down of ITGB5 may be the strategies to overcome metastasis of TSCC.

OBJECTIVE: In this study, we employed a bioinformatics approach to identify diagnostic biomarkers for tongue squamous cell carcinoma (TSCC) and investigate the infiltration of immune cells in TSCC, as well as the relationship between biomarkers and immune cells.
METHODS: We obtained the TSCC expression dataset from a database and conducted differential gene expression analysis between TSCC and adjacent normal tissues using R software. Enrichment analysis of the differentially expressed genes (DEGs) was performed using the DAVID website. Protein interaction networks for the DEGs were constructed, and hub genes were identified using tools such as STRING and Cytoscape. Survival analysis was conducted to identify diagnostic biomarkers and the infiltration of immune cells in TSCC was analyzed using the inverse convolution algorithm with Cibersort software. Finally, the expression of the discovered molecules was verified through clinical pathological sections.
RESULTS: We identified 24 DEGs in TSCC, primarily associated with signal transduction, substance metabolism, innate immune response, and other related signaling pathways. Among the 24 hub genes screened through the construction of a protein-protein interaction (PPI) network, seven (MMP13, POSTN, MMP9, MMP10, MMP3, SPP1, MMP1) exhibited prognostic value. Survival analysis indicated that SPP1 demonstrated diagnostic potential. The expression level of the SPP1 gene showed a correlation with TSCC as well as several immune cell types, including macrophage M0, M1, M2, CD8+ T cell, activated NK cell, and monocyte (p < 0.05). Histological results confirmed higher expression of SPP1 in TSCC tissues compared to adjacent non-cancerous tissues, particularly in CD68-expressing macrophages.
CONCLUSIONS: Our findings suggest that SPP1 serves as a diagnostic biomarker for TSCC and is involved in immune cell infiltration within TSCC tissues. The correlation between SPP1 and macrophages may offer new insights for targeted therapeutic research on TSCC.

Retinoic acid receptor-related orphan receptor alpha (RORα), an essential tumor suppressor in a range of human malignancies, is classified as a member of the orphan nuclear receptor family. The most prevalent form of oral cancer, tongue squamous cell carcinoma (TSCC) is characterized by its severe malignancy and unfavorable prognosis. However, the extent to which its tumorigenesis mechanisms are associated with RORα expression levels is still not fully understood. The objective of this study was to examine the molecular mechanisms by which RORα is involved in TSCC. Through the use of immunohistochemistry (IHC), it was discovered that the expression level of RORα was significantly downregulated in TSCC tissues when compared to adjacent normal tissues in this study. To further investigate the role of RORα in TSCC, we activated the expression of RORα in human TSCC cell line (SCC9 cells) by transfecting RORα cDNA and using the selective RORα agonist SR1078. The results show that RORα can significantly inhibit the invasion, migration, proliferation, and adhesion of TSCC cells and induce cell apoptosis. In addition, xenograft models confirmed the conclusion that stable activation or treatment with SR1078 to increase RORα content significantly inhibited tumor growth and development. Taken together, this study provides solid evidence for the inhibitory role of RORα in the progression of TSCC. In addition, the preliminary application results of SR1078 in TSCC show that SR1078 is expected to be a potential therapeutic medication for TSCC. These findings provide innovative perspectives on the development of potential biomarkers and agents for TSCC therapy. The objective is to introduce novel strategy and alternatives for the prevention and treatment of TSCC.

BACKGROUND: The role of Claudin-1 in tongue squamous cell carcinoma (TSCC) metastasis needs further clarification, particularly its impact on cell migration. Herein, our study aims to investigate the role of Claudin-1 in TSCC cell migration and its underlying mechanisms.
METHODS: 36 TSCC tissue samples underwent immunohistochemical staining for Claudin-1. Western blotting and immunofluorescence analyses were conducted to evaluate Claudin-1 expression and distribution in TSCC cells. Claudin-1 knockdown cell lines were established using short hairpin RNA transfection. Migration effects were assessed through wound healing assays. Furthermore, the expression of EMT-associated molecules was measured via western blotting.
RESULTS: Claudin-1 expression decreased as TSCC malignancy increased. Adenosine monophosphate-activated protein kinase (AMPK) activation led to increased Claudin-1 expression and membrane translocation, inhibiting TSCC cell migration and epithelial-mesenchymal transition (EMT). Conversely, Claudin-1 knockdown reversed these inhibitory effects on migration and EMT caused by AMPK activation.
CONCLUSIONS: Our results indicated that AMPK activation suppresses TSCC cell migration by targeting Claudin-1 and EMT pathways.

UNASSIGNED: Chemerin, as a novel multifunctional adipokine, is proposed to be involved in high cancer risk and mortality. The present study was aimed to evaluate the prognostic value of serum Chemerin and neutrophils in patients with oral squamous cell carcinoma (OSCC).
UNASSIGNED: 120 patients with OSCC were included in this prospective cohort study. The levels of serum Chemerin were measured by enzyme-linked immunosorbent assay (ELISA). We also explored the possible effects of Chemerin on neutrophils\' chemokines in OSCC using a real-time PCR, western blotting.
UNASSIGNED: Levels of serum Chemerin, neutrophils and NLR were significantly higher among non-survivors compared to survivors of OSCC (both P < 0.05). Higher serum Chemerin levels were associated with advanced TNM stage, lymph node metastasis, differentiation and tumor recurrence (both P < 0.05). Serum Chemerin levels correlated with neutrophils and NLR levels (r = 0.708, r = 0.578, both P < 0.05). Based on ROC analysis, Chemerin + NLR predicted OSCC patient mortality with 81.54 % sensitivity and 87.27 % specificity, with an AUC of 0.8898. In a Kaplan-Meier analysis, high serum Chemerin levels, high neutrophil levels and high NLR levels were associated with shorter overall and disease-free survival (both P < 0.05). A univariate and multivariate Cox regression analysis showed that serum Chemerin and neutrophils were independent risk factors for OSCC. (both P < 0.05). QRT-PCR and western blotting results showed that Chemerin upregulated the expression of chemokines IL-17 and CXCL-5 in neutrophils (both P < 0.05).
UNASSIGNED: Our study suggests that measurement of serum Chemerin and neutrophils might be a useful diagnostic and prognostic biomarker for OSCC patients. Chemerin may promote neutrophils infiltration in OSCC through upregulation of chemokines IL17 and CXCL-5.

This study aimed to investigate the role of miR-558 in tumor angiogenesis by targeting heparinase (HPSE) in tongue squamous cell carcinoma (TSCC)-derived exosomes. In the present study, the role of exosome miR-558 in angiogenesis in vitro and in vivo was investigated by cell proliferation, migration, tube formation, subcutaneous tumor formation in mice, and in vivo Matrigel plug assay. The target genes of miR-558 were detected by means of dual luciferase assay. It was found that TSCC cells secrete miR-558 into the extracellular environment, with exosome as the carrier. Human umbilical vein endothelial cells (HUVEC) ingested exosomes, which not only increased the expression level of miR-558, but also enhanced their proliferation, migration, and tube formation functions. In vivo Matrigel plug assay demonstrated that TSCC cell-derived exosome miR-558 promoted neovascularization in vivo. Compared with negative control cells, TSCC cells overexpressing miR-558 formed subcutaneous tumors in nude mice, with larger volume, heavier mass, and more vascularization. Dual luciferase assay confirmed that HPSE was the direct target gene regulated by miR-558. HPSE promoted the proliferation, migration, and tube formation of HUVECs, and the knockout of HPSE could downregulate the pro-angiogenic effect of miR-558. In summary, miR-558 in TSCC exosomes promotes the proliferation, migration, and tube formation of HUVECs by targeting HPSE, and enhancing tumor angiogenesis.

BACKGROUND: Tongue squamous cell carcinoma (TSCC) exhibits an aggressive biological behavior of lymph node and distant metastasis, which contributes to poorer prognosis and results in tongue function loss or death. In addition to known regulators and pathways of cell migration in TSCC, it is important to uncover pivotal switches governing tumor metastasis.
METHODS: Cancer cell migration-associated transcriptional and epigenetic characteristics were profiled in TSCC, and the specific super-enhancers (SEs) were identified. Molecular function and mechanism studies were used to investigate the pivotal switches in TSCC metastasis.
RESULTS: Ameboidal-type cell migration-related genes accompanied by transcriptional and epigenetic activity were enriched in TSCC. Meanwhile, the higher-ranked SE-related genes showed significant differences between 43 paired tumor and normal samples from the TCGA TSCC cohort. In addition, key motifs were detected in SE regions, and transcription factor-related expression levels were significantly associated with TSCC survival status. Notably, BATF and ATF3 regulated the expression of ameboidal-type cell migration-related MMP14 by switching the interaction with the SE region.
CONCLUSIONS: SEs and related key motifs transcriptional regulate tumor metastasis-associated MMP14 and might be potential therapeutic targets for TSCC.

Tongue squamous cell carcinoma (TSCC) is prevailing malignancy in the oral and maxillofacial region, characterized by its high frequency. LncRNA CCAT1 can promote tumorigenesis and progression in many cancers. Here, we investigated the regulatory mechanism by which CCAT1 influences growth and metastasis of TSCC. Levels of CCAT1, WTAP, TRIM46, PHLPP2, AKT, p-AKT, and Ki67 in TSCC tissues and cells were assessed utilizing qRT-PCR, Western blot and IHC. Cell proliferation, migration, and invasion were evaluated utilizing CCK8, colony formation, wound healing and transwell assays. Subcellular localization of CCAT1 was detected utilizing FISH assay. m6A level of CCAT1 was assessed using MeRIP. RNA immunoprecipitation (RIP), Co-immunoprecipitation (Co-IP) and RNA pull down elucidated binding relationship between molecules. Nude mouse tumorigenesis experiments were used to verify the TSCC regulatory function of CCAT1 in vivo. Metastatic pulmonary nodules were observed utilizing hematoxylin and eosin (HE) staining. CCAT1 silencing repressed TSCC cell proliferation, migration and invasion. Expression of CCAT1 was enhanced through N6-methyladenosine (m6A) modification of its RNA, facilitated by WTAP. Moreover, IGF2BP1 up-regulated CCAT1 expression by stabilizing its RNA transcript. CCAT1 bond to PHLPP2, inducing its ubiquitination and activating AKT signaling. CCAT1 mediated the ubiquitination and degradation of PHLPP2 by TRIM46, thereby promoting TSCC growth and metastasis. CCAT1/TRIM46/PHLPP2 axis regulated proliferation and invasion of TSCC cells, implying that CCAT1 would be a novel therapeutic target for TSCC patients.