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

Carcinoma-associated fibroblasts (CAFs) are the main cellular components of the tumor microenvironment and promote cancer progression by modifying the extracellular matrix (ECM). The tumor-associated ECM is characterized by collagen crosslinking catalyzed by lysyl oxidase (LOX). Small extracellular vesicles (sEVs) mediate cell-cell communication. However, the interactions between sEVs and the ECM remain unclear. Here, we demonstrated that sEVs released from oral squamous cell carcinoma (OSCC)-derived CAFs induce collagen crosslinking, thereby promoting epithelial-mesenchymal transition (EMT). CAF sEVs preferably bound to the ECM rather than being taken up by fibroblasts and induced collagen crosslinking, and a LOX inhibitor or blocking antibody suppressed this effect. Active LOX (αLOX), but not the LOX precursor, was enriched in CAF sEVs and interacted with periostin, fibronectin, and bone morphogenetic protein-1 on the surface of sEVs. CAF sEV-associated integrin α2β1 mediated the binding of CAF sEVs to collagen I, and blocking integrin α2β1 inhibited collagen crosslinking by interfering with CAF sEV binding to collagen I. CAF sEV-induced collagen crosslinking promoted the EMT of OSCC through FAK/paxillin/YAP pathway. Taken together, these findings reveal a novel role of CAF sEVs in tumor ECM remodeling, suggesting a critical mechanism for CAF-induced EMT of cancer cells.
Humans ; Paxillin/metabolism* ; Protein-Lysine 6-Oxidase/metabolism* ; Carcinoma, Squamous Cell/pathology* ; Epithelial-Mesenchymal Transition ; Integrin alpha2beta1/metabolism* ; Mouth Neoplasms/pathology* ; Collagen/metabolism* ; Fibroblasts ; Extracellular Vesicles/metabolism* ; Cell Line, Tumor ; Tumor Microenvironment

Oral potentially malignant disorders (OPMDs) are precursors of oral squamous cell carcinoma (OSCC). Deregulated cellular energy metabolism is a critical hallmark of cancer cells. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α) plays vital role in mitochondrial energy metabolism. However, the molecular mechanism of PGC1α on OPMDs progression is less unclear. Therefore, we investigated the effects of knockdown PGC1α on human dysplastic oral keratinocytes (DOKs) comprehensively, including cell proliferation, cell cycle, apoptosis, xenograft tumor, mitochondrial DNA (mtDNA), mitochondrial electron transport chain complexes (ETC), reactive oxygen species (ROS), oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and glucose uptake. We found that knockdown PGC1α significantly inhibited the proliferation of DOKs in vitro and tumor growth in vivo, induced S-phase arrest, and suppressed PI3K/Akt signaling pathway without affecting cell apoptosis. Mechanistically, downregulated of PGC1α decreased mtDNA, ETC, and OCR, while enhancing ROS, glucose uptake, ECAR, and glycolysis by regulating lactate dehydrogenase A (LDHA). Moreover, SR18292 (an inhibitor of PGC1α) induced oxidative phosphorylation dysfunction of DOKs and declined DOK xenograft tumor progression. Thus, our work suggests that PGC1α plays a crucial role in cell proliferation by reprograming energy metabolism and interfering with energy metabolism, acting as a potential therapeutic target for OPMDs.
Humans ; Carcinoma, Squamous Cell/metabolism* ; Cell Proliferation ; DNA, Mitochondrial ; Energy Metabolism ; Glucose ; Mouth Neoplasms/metabolism* ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism* ; Phosphatidylinositol 3-Kinases ; Reactive Oxygen Species

Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% of oral malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases were reported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by 2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ), and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oral mucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involves genetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeutic interventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCC and OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors, thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC. Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitate comprehension and provide several prospective outlooks for the fields.
Humans ; Carcinoma, Squamous Cell/therapy* ; Squamous Cell Carcinoma of Head and Neck ; Mouth Neoplasms/therapy* ; Head and Neck Neoplasms ; Tumor Microenvironment

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

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*

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