Oral Squamous Cell Carcinoma Therapy Research Articles

Light-activated photosensitizer/quercetin co-loaded extracellular vesicles for precise oral squamous cell carcinoma therapy.

Oral squamous cell carcinoma (OSCC) is the most common subtype of head and neck malignancies, characterized by a five-year survival rate that remains persistently below 50%, indicative of limited progress in therapeutic interventions. There is an urgent imperative to develop innovative therapeutic strategies, warranting the investigation of advanced treatment modalities. Nanocarriers offer a promising avenue by significantly enhancing drug properties and pharmacokinetics. Extracellular vesicles (EVs) are naturally occurring nanocarriers produced by cells and have become a focal point in drug delivery research. Quercetin, one of the most abundant dietary flavonoids, exhibits potent anticancer effects. However, its pharmaceutical application is hampered by poor water solubility, instability under physiological conditions, and low bioavailability. To overcome these obstacles, we propose using bio-derived EVs as carriers to co-encapsulate quercetin with the photosensitizer chlorin e6. This strategy leverages the intrinsic targeting capabilities of EVs for precise drug delivery to tumors, along with light-activated drug release, enabling rapid quercetin release under near-infrared light, effectively inhibiting cellular proliferation and inducing apoptosis in tumor cells. In vivo studies demonstrated that drug-loaded EVs exhibited robust tumor-targeting efficacy, resulting in effective and selective tumor ablation upon photoactivation in mice bearing subcutaneous MOC2 tumors.

Tumour-Associated Macrophages in Oral Squamous Cell Carcinoma.

Tumour-associated macrophages (TAMs) are crucial in the progression and treatment response of oral squamous cell carcinoma (OSCC). TAMs infiltrate OSCC, adopting an M2-like phenotype that promotes tumour growth, metastasis and immune suppression. The current narrative review explored the roles of TAMs in OSCC, focusing on their impact on the tumour microenvironment, invasion, metastasis, angiogenesis, immunosuppression and potential therapeutic targeting. A comprehensive analysis of the current literature on TAMs in OSCC was conducted. Specifically, we evaluated the biological functions of TAMs, their interactions within the tumour microenvironment, and their influence on disease progression and treatment outcomes. TAMs contribute to OSCC progression by secreting cytokines, such as IL-10 and TGF-β, that inhibit effector immune cells. They facilitate angiogenesis, extracellular matrix remodelling and the epithelial-mesenchymal transition, which are essential for tumour invasion and metastasis. TAMs support cancer stem cells and recruit regulatory T cells and myeloid-derived suppressor cells, enhancing resistance to therapies. Their presence correlates with advanced OSCC stages, lymph node metastasis and poor prognosis. TAMs regulate OSCC progression and therapy resistance. Reprogramming them to an M1-like phenotype or depleting them enhances treatments. Understanding TAM-OSCC interactions is crucial for developing interventions against their tumour-promoting functions and restoring anti-tumour immunity.

Structural and functional optimization of glycoprotein-enzymes for targeted biocatalysis in oral squamous cell carcinoma

The efficacy of optimized glycoproteinenzymes as a novel therapeutic approach for oral squamous cell carcinoma (OSCC) was tested in this study. The stability and viability of SCC-25 and HN4 operating-system cell lines were characterized. Both lines were confirmed to have a spindle-like morphology for SCC-25, while HN4 cells exhibited cobblestone-like clusters. Viability decreased with time for cell clones SCC-25 was 95 % and 80 % after five days, while HN4 was 94 % and 79 %. Enzyme 1, expression in E. coli and Pichia pastoris to high purity recombinant glycoprotein-enzymes. Activities of these enzymes varied equally among experimental conditions. The enzyme showed an activity of 18 units at Condition D as active max, Enzyme 2 retraced 16 units, and Enzyme 3 reached this point in the same condition. Differences in activity between different conditions were also found in various experimental conditions. In therapeutic assessments, glycoprotein-enzyme treatment lowered OSCC cell viability with IC50 values of 10–15 g/ml. Successful cellular localization could be detected primarily in the cytoplasm and nucleus of live animal tissue following treatment with those therapies. In preclinical xenograft models, treatment resulted in a 40–50 % reduction in tumour volume and growth rates, with treated tumours displaying a 60 % decrease in Ki-67, a 50 % reduction in Bcl-2, and a 70 % increase in cleaved caspase-3. Additionally, the Bax/Bcl-2 ratio increased by 80 %, and CD31 staining revealed a 40 % reduction in microvessel density. These results suggest that optimized glycoprotein enzyme therapy effectively inhibits tumour growth, induces apoptosis and reduces angiogenesis, thus laying a solid foundation for its application in clinical therapy of OSCC.

USP44 regulates HEXIM1 stability to inhibit tumorigenesis and metastasis of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most frequent type of oral malignancy with high metastasis and poor prognosis. The deubiquitinating enzyme Ubiquitin Specific Peptidase 44 (USP44) regulates the mitotic checkpoint, and its deficiency leads to aneuploidy and increases tumor incidence. However, the role of USP44 in OSCC is not well understood. Herein, we analyzed mRNA sequencing data of OSCC samples downloaded from the TCGA and GEO databases and found that USP44 was decreased in human OSCC tissues and was positively correlated to the survival of OSCC patients. To investigate the biological impact of USP44, we used recombinant lentiviruses to overexpress or knockdown USP44 expression in OSCC cell lines, which were also injected subcutaneously or into the lateral tail vein of Male BALB/c nude mice to model tumorigenesis or lung metastasis in vivo, respectively. The results showed that overexpression of USP44 inhibited malignant cell phenotypes in vitro and suppressed tumor growth and lung metastasis in vivo, while its downregulation had the opposite effects. Comprehensive proteomic analyses through Co-IP mass spectrometry and label-free quantitative LC-MS/MS methods identified 112 differentially expressed proteins positively regulated by USP44, among which 13 were involved in cancer-related pathways including apoptotic signaling and cell cycle regulation. PPI analysis identified Hexamethylene Bis-Acetamide-Inducible Protein 1 (HEXIM1) as the hub protein. Upregulation of USP44 enhanced HEXIM1 protein stability, leading to its higher expression in OSCC cells. Silencing of HEXIM1 further enhanced the malignant phenotype of OSCC cells. At the same time, HEXIM1 knockdown reversed the antitumor effects of USP44. These findings demonstrated that USP44 acted as a critical tumor suppressor in OSCC by inhibiting cell proliferation and metastasis through the stabilization of HEXIM1 protein, suggesting that USP44-HEXIM1 axis is a promising target for OSCC therapy.

Iron Knights with Nanosword Induced Ferroptosis in the Battle Against Oral Carcinoma.

Oral squamous cell carcinoma (OSCC) is a tumor characterized by cellular redox imbalance, rendering it particularly sensitive to ferroptosis treatment. However, traditional ferroptosis inducers have a few drawbacks. In this study, ultrasmall AuMn nanoclusters (AMNCs) with a bovine serum albumin (BSA) ligand were synthesized and encapsulated in natural killer (NK) cell-derived exosomes to form an Exo-AMNCs composite for targeted ferroptosis therapy of OSCC. Unlike previously reported alloyed metal nanoclusters, not only do AMNCs react with intracellular H2O2 to produce reactive oxygen species (ROS) and induce ferroptosis but also the BSA ligand improves biocompatibility and water solubility. These properties render AMNCs ideal for fluorescence imaging in vivo. When combined with NK cell exosomes, the Exo-AMNCs composite exhibited strong targeted imaging and therapeutic effects on OSCC. Further investigation into the mechanistic details demonstrated that Exo-AMNCs downregulate the overexpression of fat mass and obesity-associated (FTO) in OSCC and regulate the key ferroptosis-related protein glutathione peroxidase 4 (GPX4).

Multiomics and Molecular Docking Approaches to Elucidate Desmostachya Bipinnata-Derived Multitargeting Agents for Oral Squamous Cell Carcinoma

Background Oral squamous cell carcinoma (OSCC) is a prevalent form of head and neck cancer characterized by aggressive behavior and a poor prognosis. Conventional therapies have demonstrated limited effectiveness, underscoring the need for innovative strategies that target the molecular mechanisms involved in OSCC progression. Multitargeting agents present a promising approach by simultaneously addressing several key pathways, potentially addressing issues of treatment resistance. Desmostachya bipinnata, a medicinal plant renowned for its anticancer properties, contains bioactive compounds that may serve as effective treatments for OSCC. Objectives This study aims to investigate the therapeutic potential of bioactive compounds from Desmostachya bipinnata in treating OSCC. It uses bioinformatics and molecular docking techniques to identify key molecular targets and pathways, evaluate compound binding affinities, and propose novel multitargeting agents for OSCC therapy. Materials and Methods This study aimed to explore the therapeutic potential of Desmostachya bipinnata compounds for OSCC using bioinformatics and molecular docking. Six of the 19 compounds screened were excluded due to toxicity, leaving 14 for further analysis. GeneCards, DisGeNet, and Gene Expression Omnibus (GEO) databases identified 3,278 OSCC-related genes, and SwissTargetPrediction predicted 221 targets. Protein–protein interaction and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis pinpointed significant hub genes. Molecular docking of four selected compounds (linoleic acid, kaempferol, daucosterol, stigmasterol-glucoside) with six key targets (MMP2, PTGS2, STAT3, MAPK1, MMP9, AKT1) revealed strong binding affinities, suggesting potential therapeutic efficacy. Results This study evaluated potential therapeutic compounds from Desmostachya bipinnata for OSCC through a comprehensive approach. After assessing the toxicity of 19 compounds, six were excluded due to predicted adverse effects, leaving 14 for further analysis. We identified 3,278 OSCC-related genes by integrating data from GeneCards, DisGeNet, and GEO databases. Using SwissTargetPrediction, we narrowed down 221 unique targets for these compounds and identified 95 common targets with OSCC genes. Protein–protein interaction analysis via STRING and Cytoscape, along with Molecular Complex Detection (MCODE), highlighted a significant gene cluster. Expression analysis with Gene Expression Profiling Interactive Analysis (GEPIA) led to the exclusion of low-expressing genes (IL6, MAPK3, ESR1, BCL2), focusing on MMP2, PTGS2, STAT3, MAPK1, MMP9, and AKT1, which are involved in cancer-related pathways. Molecular docking studies showed that linoleic acid, kaempferol, daucosterol, and stigmasterol-glucoside exhibit strong binding affinities to these targets, suggesting their potential as effective therapeutic agents. Activity predictions confirmed their antineoplastic properties, underscoring their potential utility in OSCC treatment. Conclusion The findings indicate that Desmostachya bipinnata compounds exhibit promising multitargeting activity against OSCC. The strong binding affinities and interaction profiles of these compounds with key OSCC-related targets support their potential as effective therapeutic agents. Further experimental validation is needed to confirm these results and explore the clinical applicability of these compounds in OSCC treatment.

FGFR1 inhibition by carvacrol: A novel strategy for oral squamous cell carcinoma therapy

FGFR1 inhibition by carvacrol: A novel strategy for oral squamous cell carcinoma therapy

Network pharmacology and molecular docking to explore the potential molecular mechanism of chlorogenic acid treatment of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a tumor type with a high mortality rate. Chlorogenic acid, abundant in resources and widely utilized in cancer treatments, has seen limited studies regarding its efficacy against OSCC. This paper investigates chlorogenic acid's mechanism in treating OSCC, aiming to guide the development of novel drugs. The study employed network pharmacology, molecular docking, and survival analysis methods. Network pharmacological analysis revealed chlorogenic acid targets 23 OSCC-related proteins, including ESR1, MMP2, MMP9, SRC, MAPK8, MAPK1, CDC42, ERBB2, ATM, and BRAF. Molecular docking simulations indicated that the primary target exhibits significant binding capacity with chlorogenic acid, with MMP9 associated with tumor migration and angiogenesis standing out. Survival analysis demonstrated that the downregulation of most primary targets correlates with improved survival rates in OSCC patients. Enrichment analysis of therapeutic targets highlighted the pivotal role of MAPK-ERK and MAPK-JNK signaling pathways in chlorogenic acid's efficacy against OSCC. This paper predicts chlorogenic acid's potential targets and proposes its molecular mechanism in treating OSCC, offering a theoretical foundation for its application in OSCC treatment. We used traditional Chinese medicine, a disease pharmacology-related information base, and an analysis platform to predict targets. The Cytoscape 3.9.1 and STING databases were used to address common targets for drugs and diseases, establish networks of protein interaction relationships, and screen core targets. Meastro11.5 was used for molecular docking simulation. R4.2.2 was used for survival analysis and joint target enrichment analysis. Network pharmacological analysis identified chlorogenic acid acting on 23 OSCC targets. Molecular docking simulations revealed a strong binding affinity of chlorogenic acid compounds with these targets, particularly MMP9, essential for tumor migration and angiogenesis. Survival analysis indicated that the downregulation of most core targets was correlated with improved OSCC patient survival. Enrichment analysis of therapeutic targets highlighted the critical roles of the MAPK-ERK and MAPK-JNK signaling pathways in the effectiveness of chlorogenic acid against OSCC. This study predicted the potential targets of chlorogenic acid in OSCC treatment and hypothesized its molecular mechanism, offering a theoretical foundation for its use in OSCC therapy.

Nimbolide Induces Cell Apoptosis via Mediating ER Stress-Regulated Apoptotic Signaling in Human Oral Squamous Cell Carcinoma.

Human oral squamous cell carcinoma (OSCC) poses a significant health challenge in Asia, with current therapeutic strategies failing to improve the survival rates for OSCC patients sufficiently. To elucidate the effects of Nimbolide on OSCC cell proliferation and apoptosis, we performed a series of experiments, including cell proliferation assays, annexin V/PI assays, and cell cycle analysis. We further investigated nimbolide's role in modulating endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) production, and mitochondrial dysfunction using flow cytometry. Additionally, Western blotting was used to detect apoptosis-related protein expression. Our findings reveal that nimbolide exerts its anti-proliferative effects on OSCC cells by inducing apoptosis. The nimbolide increased intracellular ROS levels and acceleration of cellular calcium accumulation, respectively promoting endoplasmic reticulum stress and cancer cell apoptosis. Furthermore, nimbolide activates the caspase cascade by altering the mitochondrial membrane potential and apoptotic protein expression, thereby inhibiting the viability of tumor cells. Our data show that Nimbolide suppresses tumor growth through the induction of ROS production, ER stress, and mitochondrial dysfunction, resulting in apoptosis in OSCC cells. Overall, our study highlights nimbolide as a potential natural compound for OSCC therapy.

Dual-activity nanozyme as an oxygen pump to alleviate tumor hypoxia and enhance photodynamic/ NIR-II photothermal therapy for sniping oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the head and neck region, and its treatment is limited by hypoxia and inadequate oxygen supply. Continuous oxygen delivery combined with photodynamic therapy (PDT) is the key to addressing this issue. Here, a dual-enzyme activity sea urchin-like Au@Pt-Ce6-HN-1 nanoplatform was designed to serve as an "oxygen pump" to alleviate tumor hypoxia for synergistic photodynamic/photothermal therapy (PTT). In this design, the photosensitizer chlorin e6 (Ce6) is covalently linked to the Au@Pt nanozyme for PDT treatment. The Au@Pt nanozyme exhibits catalase-like activity, continuously decomposing H2O2 in the tumor microenvironment to enhance O2 levels, thereby achieving efficient PDT. Furthermore, Au@Pt can perform PTT and increase oxygen levels under NIR-II light to further promote PDT. The Au@Pt nanozyme also exhibits peroxidase-like activity, generating ·OH for chemodynamic therapy (CDT). Additionally, HN-1 guides the direction of "sniping" OSCC, and its high specificity benefits Au@Pt-Ce6-HN-1 at the tumor site. Au@Pt-Ce6-HN-1 exhibits bright fluorescence (FL), strong CT signal, and photothermal imaging capabilities, laying the foundation for subsequent guided PDT/PTT. This nanoplatform, which combines advantages such as continuous oxygen production, tumor targeting, and multimodal imaging, is expected to provide valuable insights into the treatment of OSCC. Statement of significanceAccurate clinical diagnosis and treatment of OSCC are challenging. We report a dual-enzyme activity sea urchin-like Au@Pt-Ce6-HN-1 nanoplatform, serving as an "oxygen pump" to guide photodynamic therapy (PDT) and photothermal therapy (PTT) for OSCC. This nanoplatform targets OSCC for preoperative CT diagnosis and offers fluorescence visualization for surgical navigation, demonstrating potential in clinical cancer detection and surgery guidance. This innovative approach addresses OSCC hypoxia and enhances treatment efficacy through continuous oxygen production, tumor targeting, and multimodal imaging, significantly improving patient outcomes in OSCC treatment.

The therapeutic effects of mesenchymal stem cells and their secretome on oral squamous cell carcinoma.

Oral cancers are prevalent in the human population, particularly in unindustrialized countries. In 90 % of oral cancers, the tumors arise from squamous cells, which is called oral squamous cell carcinoma (OSCC). Despite new treatment strategies, the morbidity and mortality rates are still high. Current treatment options including surgery, chemotherapy, and radiotherapy are not effective in the treatment of the tumor. Cell therapy with mesenchymal stem cells (MSCs) is considered one of the leading strategies in cancer treatment. However, the field of MSC therapy in OSCC is immature and ongoing studies are being conducted in experimental and pre-clinical studies. Here, we reviewed these studies to figure out whether the use of MSCs could be worthwhile in OSCC therapy or not. Both native and engineered MSCs as well as their secretome have been used in the treatment of OSCC. It seems that genetically modified MSCs or their secretome could inhibit the tumorigenesis of OSCC. However, further pre-clinical studies are required to come to a conclusion.

PPT1 Promotes Growth and Inhibits Ferroptosis of Oral Squamous Cell Carcinoma Cells.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers with poor prognosis in the head and neck. Elucidating molecular mechanisms underlying OSCC occurrence and development is important for the therapy. Dysregulated palmitoylation-related enzymes have been reported in several cancers but OSCC. To explore the role of palmitoyl-protein thioesterase 1 (PPT1) in OSCC. Differentially expressed genes (DEGs) and related protein-protein interaction networks between normal oral epithelial and OSCC tissues were screened and constructed via different online databases. Tumor samples from 70 OSCC patients were evaluated for the relationship between PPT1 expression level and patients'clinic characteristics. The role of PPT1 in OSCC proliferation and metastasis was studied by functional experiments including MTT, colony formation, EdU incorporation and transwell assays. Lentivirus-based constructs were used to manipulate gene expression. FerroOrange probe and malondialdehyde assay were used to determine ferroptosis. Growth of OSCC cells in vivo was investigated by a xenograft mouse model. A total of 555 DEGs were obtained, and topological analysis revealed that PPT1 and GPX4 might play critical roles in OSCC. Increased PPT1 expression was found to be correlated with poor prognosis of OSCC patients. PPT1 effectively promoted the proliferation, migration and invasion while inhibited the ferroptosis of OSCC cells. PPT1 affected the expression of glutathione peroxidase 4 (GPX4). PPT1 promoted growth and inhibited ferroptosis of OSCC cells. PPT1 might be a potential target for OSCC therapy.

Exploring the therapeutic potential of lipid-based nanoparticles in the management of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a highly malignant and invasive tumor with significant mortality and morbidity. Current treatment modalities such as surgery, radiotherapy, and chemotherapy encounter significant limitations, such as poor targeting, systemic toxicity, and drug resistance. There is an urgent need for novel therapeutic strategies that offer targeted delivery, enhanced efficacy, and reduced side effects. The advent of lipid-based nanoparticles (LNPs) offers a promising tool for OSCC therapy, potentially overcoming the limitations of current therapeutic approaches. LNPs are composed of biodegradable and biocompatible lipids, which minimize the risk of toxicity and adverse effects. LNPs can encapsulate hydrophobic drugs, improving their solubility and stability in the biological environment, thereby enhancing their bioavailability. LNPs demonstrate significantly higher ability to encapsulate lipophilic drugs than other nanoparticle types. LNPs offer excellent storage stability, minimal drug leakage, and controlled drug release, making them highly effective nanoplatforms for the delivery of chemotherapeutic agents. Additionally, LNPs can be modified by complexing them with specific target ligands on their surface. This surface modification allows the active targeting of LNPs to the tumors in addition to the passive targeting mechanism. Furthermore, the PEGylation of LNPs improves their hydrophilicity and enhances their biological half-life by reducing clearance by the reticuloendothelial system. This review aims to discuss current treatment approaches and their limitations, as well as recent advancements in LNPs for better management of OSCC.

Nanocarrier-based drug delivery system with dual targeting and NIR/pH response for synergistic treatment of oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is highly heterogeneous and aggressive, but therapies based on single-targeted nanoparticles frequently address these tumors as a single illness. To achieve more efficient drug transport, it is crucial to develop nanodrug-carrying systems that simultaneously target two or more cancer biomarkers. In addition, combining chemotherapy with near-infrared (NIR) light-mediated thermotherapy allows the thermal ablation of local malignancies via photothermal therapy (PTT), and triggers drug release to improve chemosensitivity. Thus, a novel dual-targeted nano-loading system, DOX@GO-HA-HN-1 (GHHD), was created for synergistic chemotherapy and PTT by the co-modification of carboxylated graphene oxide (GO) with hyaluronic acid (HA) and HN-1 peptide and loading with the anticancer drug doxorubicin (DOX). Targeted delivery using GHHD was shown to be superior to single-targeted nanoparticle delivery. NIR radiation will encourage the absorption of GHHD by tumor cells and cause the site-specific release of DOX in conjunction with the acidic microenvironment of the tumor. In addition, chemo-photothermal combination therapy for cancer treatment was realized by causing cell apoptosis under the irradiation of 808-nm laser. In summary, the application of GHHD to chemotherapy combined with photothermal therapy for OSCC is shown to have important potential as a means of combatting the low accumulation of single chemotherapeutic agents in tumors and drug resistance generated by single therapeutic means, enhancing therapeutic efficacy.

Extracellular vesicle-bound VEGF in oral squamous cell carcinoma and its role in resistance to Bevacizumab Therapy

BackgroundVascular endothelial growth factor (VEGF) is an important proangiogenic factor and has been considered as a key target of antiangiogenetic therapy in oral squamous cell carcinoma (OSCC). However, clinical application of bevacizumab, a specific VEGF antibody, didn’t improve the survival rate of OSCC patients. One possible explanation is that VEGF gene expresses diverse isoforms, which associate with extracellular vesicles (EVs), and EVs potentially contribute to VEGF resistance to bevacizumab. However, clear solution is lacking in addressing this issue.MethodsExpression of VEGF isoforms in OSCC cells was confirmed by reverse transcription and polymerase chain reaction (RT-PCR) and western blot. EVs isolated from OSCC cell’s conditioned medium (CM) were characterized by western blot, transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Flow cytometry, immunogold labeling and western blot were applied to study the VEGF on EVs. Tube formation assay and Matrigel plug angiogenesis assay were used for analyzing the angiogenesis capacity of EV-VEGF.ResultsThe most popular isoforms expressed by VEGF gene are VEGF121, VEGF165 and VEGF189. In this study, we demonstrated that all three isoforms of mRNA could be detected at varying levels in OSCC cells, while only VEGF165 and VEGF189 proteins were found. CM derived from OSCC cells, both soluble and non-soluble forms of VEGF could be detected. We further confirmed the presence of VGEF189 bound to EVs as a non-soluble form. EV-bound VEGF189 presented angiogenic activity, which could not be neutralized by bevacizumab. It was found that VEGF189 bound to EVs by heparan sulfate proteoglycans (HSPG). In addition, the angiogenic effect of EV-VEGF could be reversed by surfen, a kind of HSPG antagonist both in vitro and in vivo.ConclusionAntagonists targeting HSPG might potentially overcome the resistance of EV-VEGF to bevacizumab and serve as an alternative for anti-VEGF therapy in OSCC.

Efficacy of Cisplatin-CXCR4 Antagonist Combination Therapy in Oral Cancer.

Cisplatin is a platinum-based compound that is widely used for treating inoperable oral squamous cell carcinoma (OSCC) in Japan; however, resistance to cisplatin presents a challenge and innovative approaches are required. We aimed to investigate the therapeutic potential of targeting the chemokine receptor CXCR4, which is involved in angiogenesis and tumor progression, using the CXCR4 inhibitor AMD3100, in combination with cisplatin. AMD3100 induced necrosis and bleeding in OSCC xenografts by inhibiting angiogenesis. We investigated the combined ability of AMD3100 plus cisplatin to enhance the antitumor effect in cisplatin-resistant OSCC. An MTS assay identified HSC-2 cells as cisplatin-resistant cells in vitro. Mice treated with the cisplatin-AMD combination exhibited the most significant reduction in tumor volume, accompanied by extensive hemorrhage and necrosis. Histological examination indicated thin and short tumor vessels in the AMD and cisplatin-AMD groups. These results indicated that cisplatin and AMD3100 had synergistic antitumor effects, highlighting their potential for vascular therapy of refractory OSCC. Antitumor vascular therapy using cisplatin combined with a CXCR4 inhibitor provides a novel strategy for addressing cisplatin-resistant OSCC.

Oxidative Stress in the Pathogenesis of Oral Cancer.

Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) and antioxidants, contributes significantly to oral cancer such as oral squamous cell carcinoma (OSCC) initiation, promotion, and progression. ROS, generated both internally and externally, induce cellular damage including DNA mutations and lipid peroxidation, fostering oncogene activation and carcinogenesis. The objective of this review was to cover and analyze the interplay between ROS and antioxidants, influencing the key processes such as cell proliferation, apoptosis, and angiogenesis, shaping the trajectory of OSCC development. Despite the promise of antioxidants to halt cancer progression and mitigate oxidative damage, their therapeutic efficacy remains debated. The conducted literature search highlighted potential biomarkers that indicate levels of oxidative stress, showing promise for the early detection and monitoring of OSCC. Furthermore, melatonin has emerged as a promising adjunct therapy for OSCC, exerting antioxidant and oncostatic effects by modulating tumor-associated neutrophils and inhibiting cancer cell survival and migration. In addition, this review aims to shed light on developing personalized therapeutic strategies for patients with OSCC such as melatonin therapy, which will be discussed. Research is needed to elucidate the underlying mechanisms and clinical implications of oxidative stress modulation in the context of oral cancer.

Lactylome analyses suggest systematic lysine-lactylated substrates in oral squamous cell carcinoma under normoxia and hypoxia

Cancer cells tend to live in hypoxic environment characterized by enhanced glycolysis and accumulation of lactate. Intracellular lactate is shown to drive a novel type of post-translational modification (PTM), lysine lactylation (Kla). Kla has been confirmed to affect the malignant progression of tumors such as hepatocellular carcinoma (HCC) and colon cancer, whereas the global lactylomic profiling of oral squamous cell carcinoma (OSCC) is unclear. Here, the integrative lactylome and proteome analyses by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 1011 Kla sites within 532 proteins and 1197 Kla sites within 608 proteins in SCC25 cells under normoxic and hypoxic environments, respectively. Among these lactylated proteins, histones accounted for only a small fraction, suggesting the presence of Kla modification of OSCC in a large number of non-histone proteins. Notably, Kla preferred to enrich in spliceosome, ribosome and glycolysis/gluconeogenesis pathway in both normoxic and hypoxic cultures. Compared with normoxia, 589 differential proteins with 898 differentially lactylated sites were detected under hypoxia, which were mainly associated with the glycolysis/gluconeogenesis pathway by KEGG analysis. Importantly, we verified the presence of lactylation modification in the spliceosomal proteins hnRNPA1, SF3A1, hnRNPU and SLU7, as well as in glycolytic enzyme PFKP. In addition, the differential alternative splicing analysis described the divergence of pre-mRNA splicing patterns in the presence or absence of sodium lactate and at different oxygen concentrations. Finally, a negative correlation between tissue Kla levels and the prognosis of OSCC patients was revealed by immunohistochemistry. Our study is the first report to elucidate the lactylome and its biological function in OSCC, which deepens our understanding of the mechanisms underlying OSCC progression and provides a novel strategy for targeted therapy for OSCC.

Harnessing tetrahedral framework nucleic acids for enhanced delivery of microRNA-149-3p: A new frontier in oral squamous cell carcinoma therapy.

Oral squamous cell carcinoma (OSCC), a type of malignant tumour that primarily occurs in the oral mucosa, has drawn considerable attention owing to its aggressive growth and potentially high metastatic rate. Surgical resection is the primary treatment method for OSCC and is typically combined with radiation therapy and chemotherapy. microRNA-149-3p (miR-149) is a negative regulator of the Pi3k/Akt pathway and can effectively inhibit the proliferation of tumour cells. However, the application of miR-149 is limited owing to its relatively low efficiency of cellular uptake and poor stability when used alone. To overcome these challenges, this study adopted a novel nucleic acid nanostructured material, tetrahedral framework nucleic acids (tFNAs). The use of tFNAs as carriers to assemble the T-miR-149 complex reduced the expression of Pi3k and Akt involved in tumorigenesis and alterations in proteins related to cell apoptosis. The results indicated that the bionic drug delivery system has an effective tumour suppressive effect on OSCC in mice, revealing its potential clinical value in the treatment of OSCC.

The novel circ_0004674/miR-139-5p/ZBTB2 regulatory cascade inhibits the development of oral squamous cell carcinoma.

Circular RNAs (circRNAs) are an intriguing family of RNA molecules due to their crucial roles in the pathogenesis of oral squamous cell carcinoma (OSCC). Here, we sought to define the action of human circ_0004674 in OSCC progression. The functional role of circ_0004674 was validated by determining its effect on cell growth, apoptosis, and tube formation ability of OSCC cells. For protein quantification, a western blot or immunohistochemistry method was applied. The interaction between miR-139-5p and circ_0004674 or zinc finger and BTB domain containing 2 (ZBTB2) was predicted by online algorithms, and their relationships were confirmed by dual-luciferase reporter and RIP assays. Xenograft models were established to uncover circ_0004674's role in tumor growth. Circ_0004674 expression was upregulated in OSCC. Functionally, knocking down circ_0004674 led to suppressed OSCC cell progression in vitro and delayed tumor growth in vivo. Mechanistically, circ_0004674 post-transcriptionally controlled ZBTB2 expression by competitively pairing to miR-139-5p. Furthermore, the deficiency of miR-139-5p abated circ_0004674 silencing-mediated OSCC cell progression repression, and augmentation of ZBTB2 reversed the anticancer effect of miR-139-5p on OSCC. Our findings uncover a novel regulatory cascade, the circ_0004674/miR-139-5p/ZBTB2 axis, with the ability to affect OSCC development in vitro and in vivo, providing a potential opportunity for development of OSCC therapy.