Oral diseases, such as periodontitis, salivary gland diseases, and oral cancers, significantly challenge health conditions due to their detrimental effects on patient's digestive functions, pronunciation, and esthetic demands. Delayed diagnosis and non-targeted treatment profoundly influence patients' prognosis and quality of life. The exploration of innovative approaches for early detection and precise treatment represents a promising frontier in oral medicine. Exosomes, which are characterized as nanometer-sized extracellular vesicles, are secreted by virtually all types of cells. As the research continues, the complex roles of these intracellular-derived extracellular vesicles in biological processes have gradually unfolded. Exosomes have attracted attention as valuable diagnostic and therapeutic tools for their ability to transfer abundant biological cargos and their intricate involvement in multiple cellular functions. In this review, we provide an overview of the recent applications of exosomes within the field of oral diseases, focusing on inflammation-related bone diseases and oral squamous cell carcinomas. We characterize the exosome alterations and demonstrate their potential applications as biomarkers for early diagnosis, highlighting their roles as indicators in multiple oral diseases. We also summarize the promising applications of exosomes in targeted therapy and proposed future directions for the use of exosomes in clinical treatment.
Humans ; Exosomes ; Quality of Life ; Extracellular Vesicles ; Biomarkers ; Cell Communication ; Mouth Neoplasms

Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic tumor, has a heterogeneous internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OSCC, Single cell (SC) and spatial transcriptomics (ST) sequencing of OSCC tissues were performed. The proportion of TME in the ST data was obtained through SPOTlight deconvolution using SC and GSE103322 data. The metabolic activity of each spot was calculated using scMetabolism, and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-β expression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-β secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OSCC using SC, ST and TCGA bulk data, and highlights potential targets for therapy.
Humans ; Carcinoma, Squamous Cell/metabolism* ; Squamous Cell Carcinoma of Head and Neck ; Mouth Neoplasms/metabolism* ; Immunosuppression Therapy ; Transforming Growth Factor beta ; Head and Neck Neoplasms ; Gene Expression Profiling ; Tumor Microenvironment

Humans ; Bayes Theorem ; Age Factors ; Age Distribution ; Mouth Neoplasms/epidemiology* ; China/epidemiology* ; Mortality

OBJECTIVES: Tongue squamous cell carcinoma (TSCC) is a common cancer in the oral and maxillofacial region, which seriously endangers people's life and health.Heterogeneous nuclear ribonucleoprotein A2/B1(hnRNP A2/B1) is an RNA-binding protein that regulates the expression of a variety of genes and participates in the occurrence and development of a variety of cancers. This study aims to investigate the role of hnRNP A2/B1 in TSCC progression. METHODS: The differential expression of hnRNP A2/B1 in oral squamous cell carcinoma (OSCC) and normal oral mucosa cells and tissues was analyzed based on the gene expression profiles of GSE146483 and GSE85195 in the Gene Expression Omnibus (GEO) database. The correlation between hnRNP A2/B1 expression and disease-free survival of TSCC patients was analyzed based on TSCC related chip of GSE4676. TSCC cancer and paracancerous tissue samples of 30 patients were collected in Hunan Cancer Hospital from July to December 2021. Real-time RT-PCR and Western blotting were used to verify the mRNA and protein expression of hnRNP A2/B1 in TSCC patients'samples, respectively. Human TSCC Tca-8113 cells were transfected with hnRNP A2/B1 empty vector (a sh-NC group), knockdown plasmid (a sh-hnRNP A2/B1 group), empty vector overexpression plasmid (an OE-NC group) and overexpression plasmid (an OE-hnRNP A2/B1 group), respectively. The knockdown or overexpression efficiency of hnRNP A2/B1 was detected by Western blotting. The proliferation activity of Tca-8113 cells was detected by cell counting kit-8 (CCK-8), and the apoptosis rate of Tca-8113 cells was detected by flow cytometry. RESULTS: Based on the analysis of OSCC-related chips of GSE146483 and GSE85195 in the GEO database, it was found that hnRNP A2/B1 was differentially expressed in the OSCC and normal oral mucosa cells and tissues (all P<0.01). Meanwhile, the analysis of TSCC related chip GSE4676 confirmed that the expression of hnRNP A2/B1 was negatively correlated with the disease-free survival of TSCC patients (P=0.006). The results of real-time RT-PCR and Western blotting showed that the relative expression levels of hnRNP A2/B1 mRNA and protein in TSCC tissues were significantly up-regulated compared with those in adjacent tissues (all P<0.01). The results of Western blotting showed that the expression level of hnRNP A2/B1 in Tca-8113 cells was significantly inhibited or promoted after knockdown or overexpression of hnRNP A2/B1 (all P<0.01). The results of CCK-8 and flow cytometry showed that inhibition of hnRNP A2/B1 expression in Tca-8113 cells reduced cell proliferation activity (P<0.05) and increased cell apoptic rate (P<0.01). Overexpression of hnRNP A2/B1 in Tca-8113 cells significantly increased cell proliferation (P<0.05) and decreased cell apoptosis (P<0.01). CONCLUSIONS HnRNP A2/B1 is a key factor regulating the proliferation and apoptosis of TSCC cells. Inhibition of hnRNP A2/B1 expression can reduce the proliferation activity of TSCC cells and promote the apoptosis of TSCC cells.
Humans ; Carcinoma, Squamous Cell/genetics* ; Sincalide/metabolism* ; Tongue Neoplasms/genetics* ; Mouth Neoplasms ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/metabolism* ; RNA, Messenger ; Tongue/metabolism* ; Cell Line, Tumor

Objective: To investigate the efficacies of different forms of free radial collateral artery perforator flaps in repairing the defects after oral tumor surgeries. Methods: From May 2016 to March 2021, 28 patients (22 males, 6 females, aged 35-62 years) with oral tumors admitted by Hunan Cancer Hospital received the reconstructive surgeries with the free radial collateral artery perforator flaps after removal of oral tumors, including 24 cases of tongue cancer (11 cases of tongue marginal cancer, 9 cases of tongue belly cancer and 4 cases of tongue cancer involved in the floor of the mouth) and 4 cases of buccal and oral cancer. Four forms of radial collateral artery perforator flaps were used: single perforator flaps for 6 cases, double perforators flaps for 7 cases, flaps without perforator visualization for 10 cases and chimeric perforator myocutaneous flaps for 5 cases. The recipient vessels were the superior thyroid artery and superior thyroid vein, and if second concomitant vein available, it was anastomosed with internal jugular vein in end-to-side fashion. SPSS 20.0 statistical software was used to analyze the data. Results: The mean length of flaps was (9.7±0.4) cm, mean width (4.4±0.3) cm and mean thickness (1.1±0.4) cm. The mean length of the vascular pedicles was (7.1±0.6)cm (6.0-8.0 cm), the mean diameter of the radial accessory arteries was (1.1±0.3)mm (0.8-1.3 mm). Eleven cases(39.3%) had respectively one accompanying vein and 17 cases(60.7%) had respectively two accompanying veins, with the mean diameter of (1.1±0.3) mm (0.8-1.3 mm). All the 28 flaps survived, the donor and recipient wounds healed in one stage, the appearances of the flaps were satisfactory, only linear scars remained in the donor sites, and the upper arm functions were not significantly affected. Follow up for 12-43 months showed that the flaps were soft with partially mucosalization, the reconstructed tongue and buccal cavity were in good shape, and the swallowing and language functions were satisfactory. The swallowing and language functions were retained to the greatest extent in 3 cases with near total tongue resection, although the functions were still significantly affected. There was no local recurrence of the tumor during follow-up. One case had regional lymph node metastasis, and further lymph node dissection and comprehensive treatment were performed, with satisfactory outcomes. Conclusions: The vascular pedicle of the radial collateral artery perforator flap has a constant anatomy, which can be prepared in different forms to improve the safety of the operation and minimize the donor site damage. It is an ideal choice for the repair of small and medium-sized defects after oral tumor surgery.
Male ; Female ; Humans ; Perforator Flap/transplantation* ; Plastic Surgery Procedures ; Tongue Neoplasms/surgery* ; Arm/surgery* ; Mouth Neoplasms/surgery* ; Arteries ; Skin Transplantation ; Treatment Outcome

Objective: To investigate the anatomical classification of adductor magnus perforator flap and its application in head and neck reconstruction. Methods: From January 2017 to January 2020, Hunan Cancer Hospital treated 27 cases of oral tumor patients (15 cases of tongue cancer, 9 cases of gingival cancer and 3 cases of buccal cancer), including 24 males and 3 females, aged 31-56 years old. The course of disease was 1-12 months. Secondary soft tissue defects with the sizes of 5.0 cm × 3.5 cm to 11.0 cm × 8.0 cm were left after radical resection of the tumors, and were repaired with free adductor magnus perforator flaps. The flaps based on the origing locations of perforator vessels were divided into three categories: ① intramuscular perforator: vessel originated between the gracilis muscle and the adductor magnus or passed through a few adductor magnus muscles; ② adductor magnus middle layer perforator: vessel run between the deep and superficial layers of adductor magnus; ③ adductor magnus deep layer perforator: vessel run between the deep layer of adductor magnus and the semimembranous muscle. Descriptive analysis was used in this research. Results: Perforator vessels of adductor magnus were found in all cases, with a total of 62 perforator branches of adductor magnus. The anatomical classification of the perforator vessels was as follows: 12 branches for class ①, 31 branches for class ② and 19 branches for class ③. The vascular pedicles of the free adductor major perforator flaps included type ① for 3 cases, type ② for 16 cases and type ③ for 8 cases. All 27 flaps survived and the donor sites were closed directly. In 18 cases, the perforator arteries and the venae comitan were respectively anastomosed with the superior thyroid arteries and veins. In 9 cases, the pedicle arteries and the venae comitan were respectively anastomosed with the facial arteries and veins. Follow up for 12-40 months showed that the appearances of the flaps and the swallowing and language functions of patients were satisfactory, apart from linear scars were left in the donor sites with no significant affect on the functions of thigh. Local recurrence occurred in 3 cases and radical surgeries were performed again followed by repairs with pedicled pectoralis major myocutaneous flaps. Cervical lymph node metastasis occurred in 2 cases and cervical lymph node dissection was performed again. Conclusions: The adductor magnus perforator flap has soft texture, constant perforator vessel anatomy, flexible donor location and harvesting forms, and less damage to the donor site. It is an ideal choice for postoperative reconstruction in head and neck tumors.
Male ; Female ; Humans ; Adult ; Middle Aged ; Perforator Flap/transplantation* ; Plastic Surgery Procedures ; Thigh/surgery* ; Head/surgery* ; Skin Transplantation ; Mouth Neoplasms/surgery* ; Treatment Outcome

Tumor-associated macrophages (TAMs) play crucial roles in tumor progression and immune responses. However, mechanisms of driving TAMs to antitumor function remain unknown. Here, transcriptome profiling analysis of human oral cancer tissues indicated that regulator of G protein signaling 12 (RGS12) regulates pathologic processes and immune-related pathways. Mice with RGS12 knockout in macrophages displayed decreased M1 TAMs in oral cancer tissues, and extensive proliferation and invasion of oral cancer cells. RGS12 increased the M1 macrophages with features of increased ciliated cell number and cilia length. Mechanistically, RGS12 associates with and activates MYC binding protein 2 (MYCBP2) to degrade the cilia protein kinesin family member 2A (KIF2A) in TAMs. Our results demonstrate that RGS12 is an essential oral cancer biomarker and regulator for immunosuppressive TAMs activation.
Mice ; Humans ; Animals ; Tumor-Associated Macrophages/metabolism* ; Carcinoma, Squamous Cell ; Squamous Cell Carcinoma of Head and Neck ; Mouth Neoplasms ; GTP-Binding Proteins/metabolism* ; Head and Neck Neoplasms ; Ubiquitin-Protein Ligases/metabolism* ; Adaptor Proteins, Signal Transducing/metabolism* ; RGS Proteins/metabolism* ; Kinesins/metabolism* ; Repressor Proteins/metabolism*

Oral squamous cell carcinoma (OSCC) escape from the immune system is mediated through several immunosuppressive phenotypes that are critical to the initiation and progression of tumors. As a hallmark of cancer, DNA damage repair is closely related to changes in the immunophenotypes of tumor cells. Although flap endonuclease-1 (FEN1), a pivotal DNA-related enzyme is involved in DNA base excision repair to maintain the stability of the cell genome, the correlation between FEN1 and tumor immunity has been unexplored. In the current study, by analyzing the clinicopathological characteristics of FEN1, we demonstrated that FEN1 overexpressed and that an inhibitory immune microenvironment was established in OSCC. In addition, we found that downregulating FEN1 inhibited the growth of OSCC tumors. In vitro studies provided evidence that FEN1 knockdown inhibited the biological behaviors of OSCC and caused DNA damage. Performing multiplex immunohistochemistry (mIHC), we directly observed that the acquisition of critical immunosuppressive phenotypes was correlated with the expression of FEN1. More importantly, FEN1 directly or indirectly regulated two typical immunosuppressive phenotype-related proteins human leukocyte antigen (HLA-DR) and programmed death receptor ligand 1 (PD-L1), through the interferon-gamma (IFN-γ)/janus kinase (JAK)/signal transducer and activator transcription 1 (STAT1) pathway. Our study highlights a new perspective on FEN1 action for the first time, providing theoretical evidence that it may be a potential immunotherapy target for OSCC.
Humans ; Carcinoma, Squamous Cell/pathology* ; DNA ; Down-Regulation ; Flap Endonucleases/metabolism* ; Head and Neck Neoplasms ; Interferon-gamma/metabolism* ; Mouth Neoplasms/pathology* ; Phenotype ; Squamous Cell Carcinoma of Head and Neck ; Tumor Microenvironment ; Janus Kinases/metabolism*

Diosgenin, a steroidal sapogenin, obtained from Trigonella foenum-graecum, Dioscorea, and Rhizoma polgonati, has shown high potential and interest in the treatment of various cancers such as oral squamous cell carcinoma, laryngeal cancer, esophageal cancer, liver cancer, gastric cancer, lung cancer, cervical cancer, prostate cancer, glioma, and leukemia. This article aims to provide an overview of the in vivo, in vitro, and clinical studies reporting the diosgenin's anticancer effects. Preclinical studies have shown promising effects of diosgenin on inhibiting tumor cell proliferation and growth, promoting apoptosis, inducing differentiation and autophagy, inhibiting tumor cell metastasis and invasion, blocking cell cycle, regulating immunity and improving gut microbiome. Clinical investigations have revealed clinical dosage and safety property of diosgenin. Furthermore, in order to improve the biological activity and bioavailability of diosgenin, this review focuses on the development of diosgenin nano drug carriers, combined drugs and the diosgenin derivatives. However, further designed trials are needed to unravel the diosgenin's deficiencies in clinical application.
Male ; Humans ; Carcinoma, Squamous Cell/drug therapy* ; Diosgenin/metabolism* ; Mouth Neoplasms/drug therapy* ; Apoptosis ; Prostatic Neoplasms/drug therapy*

Oral squamous cell carcinoma (OSCC) is a prevalent malignant tumor affecting the head and neck region (Leemans et al., 2018). It is often diagnosed at a later stage, leading to a poor prognosis (Muzaffar et al., 2021; Li et al., 2023). Despite advances in OSCC treatment, the overall 5-year survival rate of OSCC patients remains alarmingly low, falling below 50% (Jehn et al., 2019; Johnson et al., 2020). According to statistics, only 50% of patients with oral cancer can be treated with surgery. Once discovered, it is more frequently at an advanced stage. In addition, owing to the aggressively invasive and metastatic characteristics of OSCC, most patients die within one year of diagnosis. Hence, the pursuit of novel therapeutic drugs and treatments to improve the response of oral cancer to medication, along with a deeper understanding of their effects, remains crucial objectives in oral cancer research (Johnson et al., 2020; Bhat et al., 2021; Chen et al., 2023; Ruffin et al., 2023).
Humans ; Mouth Neoplasms/pathology* ; Carcinoma, Squamous Cell/metabolism* ; Luteolin/therapeutic use* ; Squamous Cell Carcinoma of Head and Neck/drug therapy* ; Head and Neck Neoplasms/drug therapy* ; Cell Line, Tumor