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Object: This study aimed to examine the feasibility of the dovetailing skin incision design of radial forearm free flap (RFFF) for closing forearm wounds and performing maxillofacial reconstruction. Method: A total of 27 patients were divided into two groups. In the dovetail group (n = 16), forearm wounds were closed primarily and maxillofacial defects were reconstructed by dovetail RFFF. In the conventional group (n = 11), forearm wounds were closed by skin grafts from the abdomen or mattress suturing, and maxillofacial defects were reconstructed by conventional RFFF. Information on the healing time of the forearm wound, length of postsurgical hospitalization, esthetic assessments, and complications associated with the forearm wound and the maxillofacial region was collected at least 6 months postoperatively. Result: The average size of the flap in the dovetail group was smaller than that in the conventional group (p = 0.134), and average healing time of the forearm wound in dovetail group was significantly shorter than that in conventional group (p = 0.000). Comparing with the conventional group, there were more cases in the dovetail group demonstrating decreased sensitivity (p = 1.000). Esthetic assessments of forearm wound and maxillofacial reconstructions in the dovetail group were significantly higher than that in the conventional group (p = 0.000). Conclusion: Closure of forearm wounds and maxillofacial defects using dovetail design was found to be a feasible alternative to the conventional design.
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Objective: To investigate the feasibility of leg wound closure and reconstruction of maxillofacial soft defect by a fusiform-designed skin paddle in fibula free flap (FFF). Methods: Fifty patients who underwent FFF for reconstruction of maxillofacial soft defect were divided into two groups. The fusiform group (20 patients) was treated using a fusiform-designed skin paddle in FFF (skin paddle width less than 2 cm), and leg wound was closed using primary suturing. Reconstruction of the maxillofacial soft defect or filling of dead space was achieved by folding the fusiform skin paddle. The conventional group (30 patients) was treated using the conventional-designed skin paddle (skin paddle width no less than 2.5 cm). The leg wound was closed using mattress suturing or skin graft, while reconstruction of the maxillofacial soft defect or filling of dead space by conventional way. The average postoperative length of hospital stay, healing time of leg wound, and post-surgical complications were recorded at least 6 months after the surgery. Results: Compared with traditional method, the fusiform-designed skin paddle reduced the average healing time of the leg wound (fusiform group: 11.05 days, conventional group: 14.77 days, P < 0.05). The average length-to-width ratio in fusiform group was significantly greater than that of in conventional group (fusiform group: 5.85, conventional group: 2.93, P < 0.05), and no difference was observed on the graft size of skin paddle between two groups (fusiform group: 23.13, conventional group: 27.13, P > 0.05). The post-surgical early complications of the leg wound in the conventional group were higher than that of in the fusiform group (fusiform group: 0%, conventional group: 6.67%), while the post-surgical late complication of the donor site between the two groups showed no case. Healing disorders of maxillofacial soft reconstruction in the conventional group were higher than that of in the fusiform group (fusiform group: 5.26%, conventional group: 20.69%). Conclusions: Fusiform-designed skin paddle for closure of the leg wound and maxillofacial soft defect is a feasible alternative to the conventional- designed skin paddle. The fusiform- designed skin paddle resulted in the less postoperative length of hospital stay, shorter healing time of leg wound and less complication.
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We showed that microtubule-associated tumor suppressor gene (MTUS1/ATIP) downregulation correlated with poor survival in head and neck squamous cell carcinoma (HNSCC) patients and that MTUS1/ATIP1 was the most abundant isoform in HNSCC tissue. However, the location and function of MTUS1/ATIP1 have remain unclear. In this study, we confirmed that MTUS1/ATIP1 inhibited proliferation, growth and metastasis in HNSCC in cell- and patient-derived xenograft models in vitro and in vivo. MTUS1/ATIP1 localized in the outer mitochondrial membrane, influence the morphology, movement and metabolism of mitochondria and stimulated oxidative stress in HNSCC cells by directly interacting with MFN2. MTUS1/ATIP1 activated ROS, recruiting Bax to mitochondria, facilitating cytochrome c release to the cytosol to activate caspase-3, and inducing GSDME-dependent pyroptotic death in HNSCC cells. Our findings showed that MTUS1/ATIP1 localized in the outer mitochondrial membrane in HNSCC cells and mediated anticancer effects through ROS-induced pyroptosis, which may provide a novel therapeutic strategy for HNSCC treatment.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Mitocondrias , Piroptosis , Carcinoma de Células Escamosas de Cabeza y Cuello , Proteínas Supresoras de Tumor , Animales , Humanos , Ratones , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Proliferación Celular , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/genética , Ratones Desnudos , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genéticaRESUMEN
Tyrosine kinase inhibitors (TKIs) are frequently utilized in the management of malignant tumors. Studies have indicated that anlotinib has a significant inhibitory effect on oral squamous cell carcinoma (OSCC). However, the mechanisms underlying the development of resistance with long-term anlotinib treatment remain obscure. Our research found that METTL1 expression was heightened in anlotinib-resistant OSCC cells. We observed that METTL1 played a role in fostering resistance to anlotinib in both transgenic mouse models and in vitro. Mechanistically, the elevated METTL1 levels in anlotinib-resistant OSCC cells contributed to enhanced global mRNA translation and stimulated oxidative phosphorylation (OXPHOS) through m7G tRNA modification. Bioenergetic profiling demonstrated that METTL1 drived a metabolic shift from glycolysis to OXPHOS in anlotinib-resistant OSCC cells. Additionally, inhibition of OXPHOS biochemically negated METTL1's impact on anlotinib resistance. Overall, this study underscores the pivotal role of METTL1-mediated m7G tRNA modification in anlotinib resistance and lays the groundwork for novel therapeutic interventions to counteract resistance in OSCC.
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Resistencia a Antineoplásicos , Indoles , Metiltransferasas , Neoplasias de la Boca , Quinolinas , ARN de Transferencia , Animales , Humanos , Ratones , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Indoles/farmacología , Reprogramación Metabólica , Metiltransferasas/metabolismo , Metiltransferasas/genética , Ratones Transgénicos , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Quinolinas/farmacología , ARN de Transferencia/metabolismo , ARN de Transferencia/genéticaRESUMEN
Tracheostomy and delayed extubation (DE) are two methods for managing patients' airways postoperatively after oral and maxillofacial free flap transplantation. We aimed to determine the safety of both the tracheostomy and DE by conducting a retrospective study in patients undergoing oral and maxillofacial free-flap transfer from September, 2017 to September, 2022. The primary outcome was incidence of postoperative complication. Secondary outcome was measured as factors leading to perioperative performance of airway management. Ninety-five of 148 patients received delayed extubation perioperatively. In comparison to the tracheostomy group, the DE group had fewer overall postoperative complications (p = 0.028). During the postoperative period, fewer patients from the DE group required a return to the operating room, in comparison to those from the tracheostomy group (p = 0.045). The duration of surgery (p = 0.006), time in ICU (p = 0.015), duration of artificial nutrition (p < 0.001), duration of hospitalization (p < 0.001) in the DE group were all significantly shorter when compared with the tracheostomy group. In conclusion, when used in appropriate cases of oral and maxillofacial free flap transplantation patients, delayed extubation can be a safe and effective alternative to tracheostomy.
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Colgajos Tisulares Libres , Procedimientos de Cirugía Plástica , Humanos , Estudios Retrospectivos , Extubación Traqueal , Traqueostomía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiologíaRESUMEN
OBJECTIVE: Previous studies had revealed that anlotinib had outstanding anti-tumor efficacy on oral squamous cell carcinoma. However, the underlying mechanism is still unclear. MATERIALS AND METHODS: Anlotinib resistant OSCC cells were established and analyzed by RNA-sequencing. The correlations between SOD2 expression and anlotinib resistance were investigated in OSCC cells and PDX models. Functional assays were performed to verify the SOD2 expression and anlotinib resistance in OSCC cells. RESULTS: Anlotinib resistant genes were enriched in the biological processes of mitochondrion organization and the gene pathway of reactive oxygen species. SOD2 expression level was positively correlated with the resistance of anlotinib in OSCC cells and PDX models. Higher SOD2 expression of OSCC cells was more resistant to anlotinib. Anlotinib induced ROS generation, apoptosis and mitochondrial damage in OSCC cells, which can be enhanced by SOD2 knockdown and decreased by SOD2 overexpression. Mitochondrial damage was identified as swelling and cristae disappearance morphology under TEM, decreased mitochondrial membrane potential and lower MFN2 expression. CONCLUSIONS: SOD2 may be capable of protecting mitochondria by downregulating ROS generation, which contributes to the resistance of anlotinib in OSCC cells. SOD2 can be utilized as a potential therapeutic target to improve the anti-cancer efficacy of anlotinib in OSCC.
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BACKGROUND: N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA, but there were few studies on its role in cancer drug sensitivity and resistance. Anlotinib has been proved to have effective antitumor effects in oral squamous cell carcinoma (OSCC) in our previous study. Here, we sought to investigate the treatment target of anlotinib and the function and mechanisms of m6A modification in regulating anlotinib effect in OSCC. METHODS: Anlotinib treatment in a dose-dependent manner, western blotting, qRT-PCR and cell lost-of-function assays were used to study the treatment target of anlotinib in OSCC. RNA m6A dot blot assays, the m6A MeRIP-seq and MeRIP-qPCR, RNA and protein stability assays were used to explore the m6A modification of the treatment target of anlotinib. Cell lost-of-function assays after METTL3 depletion were conducted to investigate the effect of m6A modification level on the therapeutic effect of anlotinib in OSCC. Patient-derived tumor xenograft (PDX) models and immunohistochemistry staining were performed to study the relationship of METTL3 and antitumor sensitivity of anlotinib in vivo. RESULTS: Anlotinib targeted FGFR3 in the treatment of OSCC and inhibited tumor cell proliferation and promoted apoptosis by inactivating the FGFR3/AKT/mTOR signaling pathway. METTL3 was identified to target and modify FGFR3 m6A methylation and then decrease the stability of mRNA. METTL3 expression level was related to the anlotinib sensitivity in OSCC cells in vitro and METTL3 knockdown promoted anlotinib sensitivity of OSCC cells by inhibiting the FGFR3 expression. PDX models samples furthermore showed that METTL3 and FGFR3 levels were tightly correlated with the anlotinib efficacy in OSCC. CONCLUSIONS: In summary, our work revealed that FGFR3 was served as the treatment target of anlotinib and METTL3-mediated FGFR3 m6A modification played a critical function in the anlotinib sensitivity in OSCC.
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Background: This study aimed to screen and identify potential immune biomarker to predict the prognosis of oral squamous cell carcinoma (OSCC). Methods: Data of OSCC patient from The Cancer Genome Atlas (TCGA) database were downloaded, and the ESTIMATE algorithm was used to calculate stromal and immune scores. Differentially expressed genes (DEGs) between the high and low immune score groups were screened, and Kaplan-Meier survival analysis was performed to identify the DEGs linked to the overall survival (OS) time of OSCC patients. Then, those DEGs were validated in anther cohort. A correlation analysis was used to further screen the prognostic genes which were tightly linked to the expression of programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1). The expression profiles of the candidate genes interleukin 12 receptor subunit beta 1 (IL-12RB1), cytotoxic T-lymphocyte associated protein 4 (CTLA4), and G protein-coupled receptor 25 (GPR25) were identified in the single-cell RNA sequence OSCC dataset from GSE103322. Finally, immunohistochemistry (IHC) and immunofluorescence (IF) were applied to confirm the expression pattern of IL-12RB1 in OSCC tissue microarray. Kaplan-Meier analysis was used to assess the prognostic significance of IL-12RB1 staining score in the malignant and non-malignant cells among the patients. Results: The high immune score group showed better OS compared with that of the low immune scores group. Among 339 DEGs, 90 were identified as being tightly linked to OS time. In the validation set, 23 genes were confirmed to be closely associated with survival prognosis, and the expression levels of IL-12RB1, CTLA4, and GPR25 were commonly associated with the expression of PD-1/PD-L1. The RNA-sequencing showed that IL-12RB1 was expressed in epithelial and immune cells, whereas CTLA4 and GPR25 were relatively poorly expressed in the OSCC tissue. IHC showed that IL-12RB1 was positively expressed in both malignant and non-malignant cells. IF showed that IL-12RB1 was co-expressed with CD3, CD68, PD-1, and PD-L1 on the cytomembrane. Additionally, high score of IL-12RB1 expression in the non-malignant cells was a prognostic risk factor for OS of OSCC. Conclusions: IL-12RB1 was tightly associated with survival of OSCC and with the expression levels of PD-1/PD-L1 in the tumor immune microenvironment.
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The heterogeneity of exhausted T cells (Tex) is a critical determinant of immune checkpoint blockade therapy efficacy. However, few studies have explored exhausted T cell subpopulations in human cancers. In the present study, we examined samples from two cohorts of 175 patients with head and neck squamous cell cancer (HNSCC) by multiplex immunohistochemistry (mIHC) to investigate two subsets of Tex, CD8+PD1+TCF1+ progenitor exhausted T cells (TCF1+Texprog) and CD8+PD1+TCF1- terminally exhausted T cells (TCF1-Texterm). Moreover, fresh tumor samples from 34 patients with HNSCC were examined by flow cytometry and immunohistochemistry to further investigate their properties and cytotoxic capabilities and their correlation with regulatory T cells (Tregs) in the tumor immune microenvironment (TIME). mIHC and flow cytometry analysis showed that TCF1-Texterm represented a greater proportion of CD8+PD1+Tex than TCF1+Texprog in most patients. TCF1+Texprog produced abundant TNFα, while TCF1-Texterm expressed higher levels of CD103, TIM-3, CTLA-4, and TIGIT. TCF1-Texterm exhibited a polyfunctional TNFα+GZMB+IFNγ+ phenotype; and were associated with better overall survival and recurrence-free survival. The results also indicated that larger proportions of TCF1-Texterm were accompanied by an increase in the proportion of Tregs. Therefore, it was concluded that TCF1-Texterm was the major CD8+PD1+Tex subset in the HNSCC TIME and that these cells favor patient survival. A high proportion of TCF1-Texterm was associated with greater Treg abundance.
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Linfocitos T CD8-positivos , Neoplasias de Cabeza y Cuello , Neoplasias de Cabeza y Cuello/terapia , Humanos , Inmunoterapia/métodos , Pronóstico , Receptor de Muerte Celular Programada 1 , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Microambiente Tumoral , Factor de Necrosis Tumoral alfaRESUMEN
BACKGROUND: Cancer cells selectively promote the translation of oncogenic transcripts to stimulate cancer progression. Although growing evidence has revealed that tRNA modifications and related genes participate in this process, their roles in head and neck squamous cell carcinoma (HNSCC) remain largely uncharacterized. Here, we sought to investigate the function and mechanisms of the transfer RNA (tRNA) N7-methylguanosine (m7 G) modification in regulating the occurrence and development of HNSCC. METHODS: Cell lost-of-function and gain-of-function assays, xenograft models, conditional knockout and knockin mouse models were used to study the physiological functions of tRNA m7 G modification in HNSCC tumorigenesis. tRNA modification and expression profiling, mRNA translation profiling and rescue assays were performed to uncover the underlying molecular mechanisms. Single-cell RNA sequencing (scRNA-seq) was conducted to explore the tumor microenvironment changes. RESULTS: The tRNA m7 G methyltransferase complex components Methyltransferase-like 1 (METTL1)/WD repeat domain 4 (WDR4) were upregulated in HNSCC and associated with a poor prognosis. Functionally, METTL1/WDR4 promoted HNSCC progression and metastasis in cell-based and transgenic mouse models. Mechanistically, ablation of METTL1 reduced the m7 G levels of 16 tRNAs, inhibiting the translation of a subset of oncogenic transcripts, including genes related to the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. In addition, chemical modulators of the PI3K/Akt/mTOR signaling pathway reversed the effects of Mettl1 in mouse HNSCC. Furthermore, scRNA-seq results revealed that Mettl1 knockout in mouse tumor cells altered the immune landscape and cell-cell interaction between the tumor and stromal compartment. CONCLUSIONS: The tRNA m7 G methyltransferase METTL1 was found to promote the development and malignancy of HNSCC through regulating global mRNA translation, including the PI3K/AKT/mTOR signaling pathway, and found to alter immune landscape. METTL1 could be a promising treatment target for HNSCC patients.
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Neoplasias de Cabeza y Cuello , Proteínas Proto-Oncogénicas c-akt , Animales , Carcinogénesis/genética , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/metabolismo , Guanosina/análogos & derivados , Neoplasias de Cabeza y Cuello/genética , Humanos , Mamíferos/genética , Mamíferos/metabolismo , Metiltransferasas/efectos adversos , Metiltransferasas/genética , Metiltransferasas/metabolismo , Ratones , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN de Transferencia/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Microambiente TumoralRESUMEN
Anlotinib, a novel multitarget tyrosine kinase inhibitor, has shown promising results in the management of various carcinomas. This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell carcinoma (OSCC) and the underlying molecular mechanism. A retrospective clinical study revealed that anlotinib improved the median progression-free survival (mPFS) and median overall survival (mOS) of patients with recurrent and metastatic (R/M) OSCC, respectively. Functional studies revealed that anlotinib markedly inhibited in vitro proliferation of OSCC cells and impeded in vivo tumor growth of OSCC patient-derived xenograft models. Mechanistically, RNA-sequencing identified that oxidative stress, oxidative phosphorylation and AKT/mTOR signaling were involved in anlotinib-treated OSCC cells. Anlotinib upregulated NADPH oxidase 5 (NOX5) expression, elevated reactive oxygen species (ROS) production, impaired mitochondrial respiration, and promoted apoptosis. Moreover, anlotinb also inhibited phospho-Akt (p-AKT) expression and elevated p-eIF2α expression in OSCC cells. NOX5 knockdown attenuated these inhibitory effects and cytotoxicity in anlotinib-treated OSCC cells. Collectively, we demonstrated that anlotinib monotherapy demonstrated favorable anticancer activity and manageable toxicities in patients with R/M OSCC. The antitumor activity of anlotinib in OSCC may be mainly involved in the suppression of mitochondrial respiration via NOX5-mediated redox imbalance and the AKT/eIF2α pathway.
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Indoles , QuinolinasRESUMEN
BACKGROUND: The oncogene, malignant T-cell-amplified sequence 1 (MCTS1), has been found to be highly expressed in a variety of cancer cell lines. It has been shown to be involved in cell cycle progression and to confer a growth advantage for lymphomas and breast cancer. Nevertheless, the role of MCTS1 in contributing to the development of oral cancer remains elusive. METHODS: We analyzed the gene expression profiles of MCTS1 in normal oral keratinocytes and cancerous cells. Cellular proliferation, invasion, and migration experiments were performed to detect the effect of MCTS1 on the biological evolution of oral cancer. The in vitro results were verified by the in vivo lymphatic metastasis test. The underlying mechanism of MCTS1 in promoting oral cancer invasion and metastasis correlated with the epithelial-mesenchymal transition (EMT) process as revealed by western blotting. RESULTS: The results showed that MCTS1 was aberrantly expressed in oral cancer cells. MCTS1 overexpression significantly promoted tumor cell growth, proliferation, migration, and invasion. MCTS1-mediated lymphatic metastasis was verified in vivo using an intraplantar tumor model. Biomarkers associated with EMT progression were positively or negatively regulated upon knockdown or overexpression of MCTS1, respectively. CONCLUSIONS: Higher MCTS1 expression in oral cancer may be connected with an unfavorable prognosis due to involvement of MCTS1. MCTS1 potentiates the growth and proliferation of oral cancer cells and subsequent metastasis by regulating cell cycle and modifying the EMT process. KEYWORDS: Oral cancer; oncogene; malignant T-cell-amplified sequence 1 (MCTS1); metastasis; invasion.
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Varieties of pathological conditions, including diabetes, are closely related to oxidative stress (OS), but the osseointegration or bioadaptation of implants to OS and the related mechanism remain poorly explored. In this study, the antioxidation and osteoimmune regeneration of titanium implants with micro/nanotopographies were evaluated under H2O2-, lipopolysaccharide (LPS)- and hyperglycemia-mediated cellular OS models and in diabetic rats as a representative animal model of OS. TiO2 nanotube (TNT) coating on titanium implants directly induced superior osteogenic differentiation of bone mesenchymal stem cells (MSCs) and osseointegration compared with microscale sand blasted-acid etched topography (SLA) under OS, attributed to higher superoxide dismutase 2 activity, the neutralization of intracellular reactive oxygen species (ROS), and less apoptosis. Mechanistically, the oxidation resistance on TNT is driven by upregulated forkhead box transcription factor O1 (FoxO1), which is abolished after knockdown of FoxO1 via shRNA in MSCs. Indirectly, TNT also alleviates OS in macrophages, therefore inducing a higher portion of the M2 phenotype under OS with increased secretion of the anti-inflammatory cytokine IL-10, further promoting the osseoimmunity capacity compared with SLA. The current study not only suggests the potential application of TiO2 nanotube-coated titanium implants in compromised conditions but also provides a systematic evaluation strategy for the future development of bone biomaterials.
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Arecoline, the main alkaloid of areca nut, is well known for its role in inducing submucosal fibrosis and oral squamous cell carcinoma (OSCC), however the mechanism remains unclear. The aim of this study was to establish an arecoline-induced epithelial-mesenchymal transformation (EMT) model of OSCC cells and to investigate the underlying mechanisms. CAL33 and UM2 cells were induced with arecoline to establish an EMT cell model and perform RNA-sequence screening. Luminex multiplex cytokine assays, western blot, and RT-qPCR were used to investigate the EMT mechanism. Arecoline at a concentration of 160 µg/ml was used to induce EMT in OSCC cells, which was confirmed using morphological analysis, transwell assays, and EMT marker detection. RNA-sequence screening and Luminex multiplex cytokine assays showed that many inflammatory cytokines (such as serum amyloid A1 [SAA1], interleukin [IL]-6, IL-36G, chemokine [CCL]2, and CCL20) were significantly altered during arecoline-induced EMT. Of these cytokines, SAA1 was the most highly upregulated. SAA1 overexpression induced EMT and promoted the migration and invasion of CAL33 cells, while SAA1 knockdown attenuated arecoline-induced EMT. Moreover, arecoline enhanced cervical lymph node metastasis in an orthotopic xenograft model of the tongue established using BALB/c nude mice. Our findings revealed that arecoline induced EMT and enhanced the metastatic capability of OSCC by the regulation of inflammatory cytokine secretion, especially that of SAA1. Our study provides a basis for understanding the mechanism of OSCC metastasis and suggests possible therapeutic targets to prevent the occurrence and development of OSCC associated with areca nut chewing.
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Arecolina/toxicidad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias de la Boca/inducido químicamente , Proteína Amiloide A Sérica/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/inducido químicamente , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Citocinas/genética , Citocinas/metabolismo , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Metástasis Linfática , Ratones , Ratones Desnudos , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Proteína Amiloide A Sérica/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
Aim: To evaluate the biological function of titanium implants coated with cell-derived mineralized extracellular matrix, which mimics a bony microenvironment. Materials & methods: A biomimetic titanium implant was fabricated primarily by modifying the titanium surface with TiO2 nanotubes or sand-blasted, acid-etched topography, then was coated with mineralized extracellular matrix constructed by culturing bone marrow mesenchymal stromal cells. The osteogenic ability of biomimetic titanium surface in vitro and in vivo were evaluated. Results:In vitro and in vivo studies revealed that the biomimetic titanium implant enhanced and accelerated osteogenesis of bone marrow stromal cells by increasing cell proliferation and calcium deposition. Conclusion: By combining surface topography modification with biological coating, the results provided a valuable method to produce biomimetic titanium implants with excellent osteogenic ability.
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Osteogénesis , Titanio , Biomimética , Diferenciación Celular , Proliferación Celular , Materiales Biocompatibles Revestidos , Matriz Extracelular , Propiedades de SuperficieRESUMEN
RNA modification plays an essential function in regulating gene expression and diverse biological processes. RNA modification enzyme methyltransferase-like 3 (METTL3) affects tumor progression by regulating the N6-methyladenosine (m6A) modification in the mRNAs of critical oncogenes or tumor suppressors, but its effect in oral squamous cell carcinoma (OSCC) remains unknown. In this study, we revealed that METTL3 was consistently upregulated in two OSCC cohorts, and high METTL3 expression was associated with poor prognosis. Functionally, cell proliferation, self-renewal, migration, and invasion ability in vitro and tumor growth and metastasis in vivo were decreased after METTL3 knockdown in OSCC cells. In contrast, the opposite results were obtained after METTL3 overexpression. In addition, the results obtained with the Mettl3 genetically modified mouse model validated the essential role of Mettl3 in chemical-induced oral carcinogenesis. In mechanism, methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-quantitative real-time PCR, and luciferase reporter and mutagenesis assays identified that METTL3 mediates the m6A modification in the 3' UTR of BMI1 mRNA. METTL3 promotes BMI1 translation in OSCC under the cooperation with m6A reader IGF2BP1. Our findings revealed that METTL3 promotes OSCC proliferation and metastasis through BMI1 m6A methylation, suggesting that the METTL3-m6A-BMI1 axis may serve as a prognostic biomarker or therapeutic target in patients with OSCC.
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Adenosina/análogos & derivados , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Metiltransferasas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Adenosina/metabolismo , Animales , Sitios de Unión , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Humanos , Metilación , Metiltransferasas/genética , Ratones , Neoplasias de la Boca/etiología , Neoplasias de la Boca/metabolismo , Unión ProteicaRESUMEN
BACKGROUND: Patients with diabetes mellitus (DM) have a higher failure rate of dental implant treatments. However, whether titanium (Ti) implants with TiO2 nanotubes (TNT) surface can retain their biocompatibility and osteogenetic ability under DM conditions has not been investigated; in addition, their behavior in DM conditions is not well characterized. MATERIALS AND METHODS: Pure Ti discs were surface treated into the polishing (mechanically polished, MP), sandblasted and acid-etched (SLA), and TNT groups. Scanning electron microscopy was used to examine the surface morphology. The cell adhesion and proliferation ability on different modified Ti surfaces at various glucose concentrations (5.5, 11, 16.5, and 22 mM) was detected by the CCK-8 assay. The osteogenetic ability on different modified Ti surfaces under high-glucose conditions was evaluated by alkaline phosphatase (ALP), osteopontin (OPN) immunofluorescence, Western blot, and Alizarin Red staining in vitro. Detection of cell apoptosis and intracellular reactive oxygen species (ROS) was undertaken both before and after N-acetylcysteine (NAC) treatment to assess the oxidative stress associated with different modified Ti surfaces under high-glucose conditions. An in vivo study was conducted in DM rats with different modified Ti femoral implants. The osteogenetic ability of different modified Ti implants in DM rats was assessed using a micro-CT scan. RESULTS: High-glucose conditions inhibited cell adhesion, proliferation, and osteogenetic ability of different modified Ti surfaces. High-glucose conditions induced higher apoptosis rate and intracellular ROS level on different modified Ti surfaces; these effects were alleviated by NAC. Compared with the SLA surface, the TNT surface alleviated the osteogenetic inhibition induced by high-glucose states by reversing the overproduction of ROS in vitro. In the in vivo experiment, micro-CT scan analysis further confirmed the best osteogenetic ability of TNT surface in rats with DM. CONCLUSION: TNT surface modification alleviates osteogenetic inhibition induced by DM. It may provide a more favorable Ti implant surface for patients with DM.
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Diabetes Mellitus/patología , Nanotubos/química , Osteogénesis/efectos de los fármacos , Titanio/farmacología , Fosfatasa Alcalina/metabolismo , Animales , Apoptosis/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Glucosa/toxicidad , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Osteopontina/metabolismo , Prótesis e Implantes , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismo , Propiedades de SuperficieRESUMEN
AIMS: To investigate the therapeutic potential of itraconazole in oral squamous cell carcinoma (OSCC) and its molecular mechanism. MATERIALS AND METHODS: The in vitro anti-cancer effects of itraconazole was determined by CCK-8 assay and colony formation assay. Transwell and wound healing assays were used to examine cell invasion and migration. The in vivo therapeutic efficacy of itraconazole was assessed by OSCC patient-derived xenograft (PDX) model. Western blot was performed to explore the anti-cancer mechanism. KEY FINDINGS: Itraconazole inhibited cell proliferation and colony formation of OSCC cells in a time and concentration dependent manner; induced cell cycle arrest and apoptosis, as well as inhibited cell invasion and migration. In the OSCC PDX model, itraconazole impeded tumor growth, reduced Ki-67 expression and induced apoptosis. Itraconazole downregulated the protein expression of Hedgehog pathway to inhibit proliferation and migration of oral squamous cell carcinoma cells, which can be revised by recombinant human sonic hedgehog protein (rSHH). SIGNIFICANCE: Itraconazole showed anti-cancer effects on OSCC via inhibiting the Hedgehog pathway.
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Antifúngicos/farmacología , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/patología , Proteínas Hedgehog/antagonistas & inhibidores , Itraconazol/farmacología , Neoplasias de la Boca/patología , Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias de la Boca/metabolismoRESUMEN
Good biological properties for titanium implants will shorten the treatment cycle and improve patient comfort, which are also the main goals of dentistry and orthopaedics. At present, the biological properties of titanium implants are mainly enhanced in two aspects: their surface chemistry and surface morphology. In this study, a surface modification strategy combining bioactive trace elements with surface micromorphology modification was used to enhance the biological properties of pure titanium. A new coating incorporating silicon micropore/microsphere topography was prepared on a titanium plate by micro-arc oxidation (MAO) technology. The properties of the coating and its effects on the adhesion and osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) were further analyzed. The experimental results show that a coating doped with amorphous silicon with micropore/microsphere topography was incorporated onto the titanium surface and the surface roughness in the treated groups was obviously higher than that in the Ti group. In vitro, the presence of a silicon-incorporating coating with a micropore/microsphere topography on the titanium surface significantly enhanced the initial adhesion, proliferation and osteogenic differentiation of BMSCs. These results indicate that the silicon-incorporating coating with micropore/microsphere topography has potential applications in dentistry and orthopaedics.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Microesferas , Osteogénesis/efectos de los fármacos , Silicio/química , Titanio/farmacología , Animales , Adhesión Celular/efectos de los fármacos , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Ratas , Propiedades de Superficie , Titanio/químicaRESUMEN
OBJECTIVE: To provide a prognostic biomarker and a potential therapeutic target for tongue squamous cell carcinoma (TSCC). DESIGN: Screening the prognostic genes of TSCC by bioinformatics, and verifying the correlation between the above genes and the prognosis of TSCC by experiments. RESULTS: Twenty-four common differentially expressed genes (DEGs) between TSCC and the corresponding normal tissues were screened from four sets of TSCC functional gene expression series in Gene Expression Omnibus (GEO) datasets. Further bioinformatics research based on the data from The Cancer Genome Atlas (TCGA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) indicate that the low expression of SFRP1 might be correlated with poor prognosis of TSCC patients. By colony formation assay, reverse transcription polymerase chain reaction (RT-PCR), western blotting, immunohistochemical staining, flowcytometry, lentivirus transfection and animal experiments, it was confirmed that the low level of SFRP1 expression correlated with poor prognosis of TSCC patients. CONCLUSION: This study identified SFRP1 as a novel prognostic biomarker and a potential therapeutic target for TSCC.