Circular RNAs (circRNA) are a new member of endogenously produced noncoding RNAs that have been characterized as key regulators of gene expression in a variety of malignances. However, the role of circRNA in oral squamous cell carcinoma (OSCC) remains largely unknown. In this study, we identified unique circRNA that regulate OSCC progression and metastasis and pave roads for future research in early diagnosis, prevention, and treatment of OSCC. Transcriptomic analyses identified a circRNA derived from IGHG locus (circIGHG) as significantly upregulated in OSCC and positively associated with poor prognosis of OSCC. circIGHG directly bound miR-142-5p and consequently elevated IGF2BP3 activity. Knockdown of circIGHG led to impaired expression of IGF2BP3 and attenuated aggressiveness of OSCC cells. Epithelial–mesenchymal transition was the main mechanism through which circIGHG/IGF2BP3 promotes metastasis of OSCC. Overall, these results demonstrate that circIGHG plays a pivotal role in OSCC development and metastasis and has potential to serve as a biomarker and therapeutic target for early-stage diagnosis and treatment of OSCC. Significance: These findings broaden our insights regarding regulation of OSCC progression by circular RNA and serve as a reference for future clinical research in OSCC diagnosis and treatment.
Background Chemokine (C-C motif) ligand 18 (CCL18) affects the malignant progression of varying cancers by activating chemokine receptors. Our previous work has shown that CCL18 promotes hyperplasia and invasiveness of oral cancer cells; however, the cognate receptors of CCL18 involved in the pathogenesis of oral squamous cell carcinoma (OSCC) have not yet been identified. This study aimed to investigate the molecular mechanisms which underlie promotive effects of CCL18 on OSCC progression by binding to functional receptors. Methods The expression of CCL18 receptor-NIR1 in OSCC was determined by conducting western blot, immunofluorescence, and immunocytochemistry assays. Chi square test was applied to analyze the relationship between expression levels of NIR1 and clinicopathological variables. Recombinant CCL18 (rCCL18), receptor siRNA and JAK specific inhibitor (AG490) were used in experiments investigating the effects of the CCL18-NIR1 axis on growth of cancer cells (i.e., proliferation, and metastasis), epithelial-mesenchymal transition (EMT) and the activation of the JAK2/STAT3 signaling pathway. Results NIR1 as functional receptor of CCL18 in OSCC, was found to be significantly upregulated in OSCC and positively related to the TNM stage of OSCC patients. rCCL18 induced the phenotypical alterations in oral cancer cells including cell growth, metastasis and EMT. The JAK2/STAT3 signaling pathway was confirmed to be a downstream pathway mediating the effects of CCL18 in OSCC. AG490 and knockdown of NIR1 could block the effects of rCCL18-induced OSCC. Conclusion CCL18 can promote the progression of OSCC by binding NIR1, and the CCL18-NIR1 axis can activate JAK2/STAT3 signaling pathway. The identification of the mechanisms underlying CCL18-mediated promotion of OSCC progression could highlight potential therapeutic targets for treating oral cancer.
Background: The mechanisms through which immunosuppressed patients bear increased risk and worse survival in oral squamous cell carcinoma (OSCC) are unclear. Here, we used deep learning to investigate the genetic mechanisms underlying immunosuppression in the survival of OSCC patients, especially from the aspect of various survival-related subtypes.Materials and methods: OSCC samples data were obtained from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and OSCC-related genetic datasets with survival data in the National Center for Biotechnology Information (NCBI). Immunosuppression genes (ISGs) were obtained from the HisgAtlas and DisGeNET databases. Survival analyses were performed to identify the ISGs with significant prognostic values in OSCC. A deep learning (DL)-based model was established for robustly differentiating the survival subpopulations of OSCC samples. In order to understand the characteristics of the different survival-risk subtypes of OSCC samples, differential expression analysis and functional enrichment analysis were performed.Results: A total of 317 OSCC samples were divided into one inferring cohort (TCGA) and four confirmation cohorts (ICGC set, GSE41613, GSE42743, and GSE75538). Eleven ISGs (i.e., BGLAP, CALCA, CTLA4, CXCL8, FGFR3, HPRT1, IL22, ORMDL3, TLR3, SPHK1, and INHBB) showed prognostic value in OSCC. The DL-based model provided two optimal subgroups of TCGA-OSCC samples with significant differences (p = 4.91E-22) and good model fitness [concordance index (C-index) = 0.77]. The DL model was validated by using four external confirmation cohorts: ICGC cohort (n = 40, C-index = 0.39), GSE41613 dataset (n = 97, C-index = 0.86), GSE42743 dataset (n = 71, C-index = 0.87), and GSE75538 dataset (n = 14, C-index = 0.48). Importantly, subtype Sub1 demonstrated a lower probability of survival and thus a more aggressive nature compared with subtype Sub2. ISGs in subtype Sub1 were enriched in the tumor-infiltrating immune cells-related pathways and cancer progression-related pathways, while those in subtype Sub2 were enriched in the metabolism-related pathways.Conclusion: The two survival subtypes of OSCC identified by deep learning can benefit clinical practitioners to divide immunocompromised patients with oral cancer into two subpopulations and give them target drugs and thus might be helpful for improving the survival of these patients and providing novel therapeutic strategies in the precision medicine area.
Objective. To investigate the function and regulatory mechanisms of methylenetetrahydrofolate dehydrogenase (MTHFD) family genes in oral squamous cell carcinoma (OSCC), especially focus on their regulating role in tumor immunity. Methods. The publicly available data from the TCGA database were used to investigate the expression pattern and regulatory role of MTHFD family genes in OSCC. More importantly, the involvement of MTHFD family genes in tumor immunity was investigated in terms of immune and stromal cell infiltration in tumor microenvironment, tumor-infiltrating immune cells, and immunomodulatory genes (e.g., immunoinhibitory genes and immunostimulatory genes). Statistical analysis was performed using R software packages and public web servers. Results. MTHFD family genes were considerably upregulated in OSCC as compared with normal oral tissue. Patients with high MTHFD2 expression presented worse survival outcomes than those with low MTHFD2 expression. Functional enrichment analysis showed that the top 100 positively and negatively correlated genes of the MTHFD family genes were significantly enriched in several KEGG pathways, including cell cycle, spliceosome, DNA replication, and Th17 cell differentiation. As a result of tumor immunity analysis, MTHFD2L expression was found to be negatively related to the Estimate-Stromal-Immune score in OSCC; however, there was no statistical significance between the Estimate-Stromal-Immune score and MTHFD1, MTHFD1L, or MTHFD2 in OSCC. Additionally, MTHFD family genes were found to be significantly positively correlated with tumor-infiltrating immune cells, including Treg and Th17 cells. Moreover, MTHFD family genes were significantly correlated with several immune inhibitory genes such as CD274 and CTLA4 and several immune-stimulatory genes such as CXCL12, CXCR4, and TMIGD2. Conclusion. Given the expression pattern, prognostic value, biological functions, and involvement in tumor immunity, MTHFD family genes could serve as potential therapeutic biomarkers in targeting tumor immunity in oral cancer.
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