ABSTRACT
Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent and heterogeneous malignancy with a dismal overall survival rate. Nevertheless, the effective biomarkers remain ambiguous and merit further investigation. Cuproptosis is a novel defined pathway of programmed cell death that contributes to the progression of cancers. Meanwhile, long non-coding RNAs (lncRNAs) play a crucial role in the biological process of tumors. Nevertheless, the prognostic value of cuproptosis-related lncRNAs in HNSCC is still obscure. This study aimed to develop a new cuproptosis-related lncRNAs (CRLs) signature to estimate survival and tumor immunity in patients with HNSCC. Herein, 620 cuproptosis-related lncRNAs were identified from The Cancer Genome Atlas database through the co-expression method. To construct a risk model and validate the accuracy of the results, the samples were divided into two cohorts randomly and equally. Subsequently, a prognostic model based on five CRLs was constructed by the Cox regression analysis with the least absolute shrinkage and selection operator (LASSO) algorithm. In addition, the prognostic potential of the five-CRL signature was verified via Cox regression, survival analysis, the receiver operating characteristic (ROC) curve, nomogram, and clinicopathologic characteristics correlation analysis. Furthermore, we explored the associations between the signature risk score (RS) and immune landscape, somatic gene mutation, and drug sensitivity. Finally, we gathered six clinical samples and different HNSCC cell lines to validate our bioinformatics results. Overall, the proposed novel five-CRL signature can predict prognosis and assess the efficacy of immunotherapy and targeted therapies to prolong the survival of patients with HNSCC.
ABSTRACT
Oral squamous cell carcinoma (OSCC) in the background of oral submucous fibrosis (OSF) caused by areca nut chewing has a high incidence in Asia-Pacific countries. However, the molecular mechanism remains unclear. Here, we performed circRNA microarray analysis to screen the circRNA expression profiles in OSCC and OSF. We identified circEPSTI1 as a circRNA with consistent, sequential upregulation from normal buccal mucosa (NBM) to OSF to OSCC. Functionally, circEPSTI1 significantly promoted OSCC cell proliferation and invasion, as evidenced by the CCK8, colony formation, wound healing, and transwell assays with circEPSTI1 overexpression and silencing. OSCC patients with circEPSTI1high status exhibited poor prognoses. CircEPSTI1 sponged miR-942-5p and accelerated epithelial-mesenchymal transition (EMT) to increase LTBP2 expression in OSCC through phosphorylation of PI3K/Akt/mTOR signaling pathway components. Blocking the PI3K/Akt/mTOR signaling pathway with the dual PI3k/mTOR inhibitor BEZ235 reversed OSCC progression induced by overexpression of circEPSTI1 and LTBP2. Collectively, these results indicate that the circEPSTI1/miR-942-5p/LTBP2 axis affects OSCC cell proliferation and invasion via the acceleration of EMT and the phosphorylation of PI3K/Akt/mTOR signaling pathway components. CircEPSTI1 may be an independent diagnostic and prognostic marker and a potential therapeutic target for OSCC patients with OSF.
Subject(s)
MicroRNAs/genetics , Neoplasm Proteins/genetics , Squamous Cell Carcinoma of Head and Neck/genetics , Adult , Aged , Carcinoma, Squamous Cell/pathology , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , China , Disease Progression , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic/genetics , Humans , Male , MicroRNAs/metabolism , Middle Aged , Mouth Neoplasms/metabolism , Neoplasm Proteins/metabolism , Oral Submucous Fibrosis/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Circular/genetics , Signal Transduction/genetics , Squamous Cell Carcinoma of Head and Neck/pathology , TOR Serine-Threonine Kinases/metabolismABSTRACT
OBJECTIVES: Fibrosis diseases are one of the leading causes of suffering and death. However, no systematic investigation has been carried out on fibrosis-related genes. MATERIALS AND METHODS: By querying PubMed using keywords "fibrosis" and "gene" or "protein," we identified fibrosis-related genes in the last decade. Bioinformatics analysis was performed by MAS 3.0 software. Key miRNA was selected to assess its relationship with oral submucous fibrosis (OSF) and fibroblast functions. RESULTS: A total of 1,310 genes related to fibrosis were identified. TGF-ß1, CTGF, MMP9, HSP47, and S1P were found to be associated with mainly fibrotic organs. In total, 244 cellular components terms, 595 molecular function terms, 1,816 cellular component terms, and 136 KEGG pathway annotations were predicted. miR-199-5p was selected as the key miRNA, which has higher level in OSF. Upregulated miR-199-5p was significantly related to OSF duration and OSF histological grade (p = 0.028 and 0.012, respectively). Overexpressive miR-199-5p reduced proliferation and induced apoptosis in buccal fibroblasts. Additionally, expression levels of collagen I (COL I) and III (COL III) were promoted by overexpressive miR-199-5p in buccal fibroblasts. CONCLUSION: These results indicate that fibrosis-related genes are related to a series of complex mechanisms. The characteristics of miR-199-5p may supply important clues for developing therapeutic strategy for OSF.
