Background Oral squamous cell carcinoma (OSCC) is the main type of oral cancer. Disturbing DNA repair is an invaluable way to improve the effectiveness of tumor treatment. Here, we aimed to explore the key enhancer drivers associated with DNA damage repair in OSCC cells. Methods Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA) and Kaplan-Meier analysis were applied to explore the relationship among DNA repair-related genes expression and clinical phenotypes based on The Cancer Genome Atlas (TCGA) database. HOMER software and Integrative Genomics Viewer were applied to identify and visualize enhancers using GSE120634. Toolkit for Cistrome Data Browser was applied to predict transcription factors. Human Protein Atlas Database was used to analyze the protein levels of transcription factors in OSCC and control tissues. Seventy-two OSCC patients were included in this study. qRT-PCR was used to detect transcription factor expression in OSCC and adjacent control tissues collected in this study. qRT-PCR and ChIP-qPCR were used to verify the binding of transcription factors to enhancers, and regulation of target genes transcription. Transcription factor knockdown and control cells were treated with cisplatin. CCK8 was used to detect cell viability and proliferation. Western blotting was implemented to detect the levels of DNA repair-related proteins. Transwell assay was used to detect cell invasion. Results DNA repair was positively associated with the OSCC metastatic phenotype. Patients in the cluster with high expression of DNA repair-related genes had a worse prognosis and a higher proportion of advanced stage, low-differentiation, alcohol consumption and smoking compared to the cluster with low DNA repair-related gene expression. Seventeen metastasis-specific enhancer-controlled upregulated DNA repair-related genes, with the top two upregulated genes being ADRM1 26 S proteasome ubiquitin receptor (ADRM1) and solute carrier family 12 member 7 (SLC12A7) were screened. High mobility group 20 A (HMG20A) was the key prognostic enhancer driver regulating metastasis-specific DNA repair-related genes, with higher expression in OSCC tissues than normal control tissues, and higher expression in metastatic OSCC tissues than non-metastatic OSCC tissues. HMG20A bound to the metastasis-specific enhancers of ADRM1 and SLC12A7, thereby promoting ADRM1 and SLC12A7 expression. Knockdown of HMG20A enhanced cisplatin sensitivity of cells, and inhibited OSCC cells from repairing DNA damage caused by cisplatin, as well as proliferation and invasion of OSCC cells. Conclusion HMG20A was identified as the key prognostic enhancer driver regulating DNA repair in OSCC cells, providing a new therapeutic target for OSCC.
The present study aims at the preparation of a chitosan-PLGA-based proanthocyanidin from hawthorn fruit loaded nano-system (CS-PLGA-PHL) and investigate its inhibitory effect on SCC-25 cells and the related mechanisms. Methods: CS-PLGA-PHL nanocomposites were constructed by emulsion-solvent evaporation. The effect of CS-PLGA-PHL on the proliferation of human normal squamous epithelial hNOK cells were detected. The antitumor activity of CS-PLGA-PHL on SCC-25 cells were studied by cytotoxicity test, cell cycle and apoptosis analysis. The apoptotic protein and gene expression in SCC-25 cells was detected by western blotting and q-PCR. Results: The particle size distribution of CS-PLGA-PHL was narrow with an average of 177.60±41.00 nm. CS-PLGA-PHL did not show significant cytotoxicity to hNOK cells (IC50 > 50 μg/mL), with strong cytotoxicity to SCC-25 cells (IC50 = 1.21 μg/mL), which could block the G0/G1 phase of SCC-25 cells and increase the distribution of G2/M phase. Meanwhile, the apoptosis induction of CS-PLGA-PHL was higher than that of free PHL and PLGA-PHL group (P <0.05). The cell cycle inhibition and apoptosis induction may be due to the up regulation of apoptosis-associated proteins and genes. Conclusion: CS-PLGA-PHL nanocomposites can inhibit the cell cycle and promote apoptosis of SCC-25 cells by up regulating the expression of apoptosis-associated proteins and genes, suggesting that it has potential as a chemotherapeutic drug for the treatment of oral squamous cell carcinoma.
Background: Multidrug resistance (MDR) is one of the primary causes of tumor chemotherapy failure. Therefore, it is essential to uncover new drug treatment protocols. In the current study, employing chitosan (CS) and sodium tripolyphosphate (TPP) as carriers and cross-linking agents, the proanthocyanidins (PHL)/poly (lactic-co-glycolic acid) (PLGA) were encapsulated by emulsion solvent evaporation, through which the cationic CS-PLGA-PHL nanosystem was obtained. The effectiveness of CS-PLGAPHL on the invasion and migration of human oral squamous cell carcinoma cells was discussed, as were their potential mechanisms. Methods: A CS-PLGA-PHL nanosystem was constructed by emulsion-solvent evaporation. The size distribution, dispersion, and morphology were characterised by the laser particle size analyser and transmission electron microscope. Human oral squamous cell carcinoma drug-resistant cell lines SCC131/R and SCC-15/DDP were cultured in vitro. The two cell types were induced at different concentrations by CS-PLGA-PHL, after which a CCK⁃8 experiment was performed to determine the effect of CS-PLGAPHL on the proliferation of the two cell lines. The 50% inhibitory concentration (IC50) of CS-PLGAPHL was calculated at different time points. The transwell chamber experiment was performed to identify the effects of CS-PLGA-PHL on the migration and invasion of OSCC cells. The expression levels of MMP-2 and MMP-9 were detected by Western blot and q-PCR. objective: The preparation of nano system to reduce the proliferative activity of OSCC cells together with inhibit the migration, invasion and tumor growth of OSCC cells Results: CS-PLGA-PHL is well dispersed. The PDI appeared to be lowest when the mass ratio of chitosan to PLGA equaled 1:15. CS-PLGA-PHL exhibited a marked effect in inhibiting the proliferation of SCC131/R and SCC-15/DDP as well as the invasion and migration. CS-PLGA-PHL was able to downregulate the expression of MMP-2 and MMP-9 genes and proteins significantly in drug-resistant cell lines. Conclusion: CS-PLGA-PHL for oral squamous cell carcinoma has been successfully prepared to exert significant inhibition on the proliferation, invasion, and migration of OSCC cells. The mechanism involved was possibly related to the down-regulation of MMP-2 and MMP-9 expression by CS-PLGA-PHL. result: CS-PLGA-PHL is well dispersed. The PDI appeared to be lowest when the mass ratio of chitosan to PLGA equaled 1 ∶ 15. CS-PLGA-PHL exhibited a marked effect in inhibiting the proliferation of SCC-131/R and SCC-15/DDP as well as the invasion and migration. CS-PLGA-PHL of was able to downregulate the expression of MMP-2 and MMP-9 genes and proteins significantly in drug-resistant cell lines other: None
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