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Novel Transcripts of EMT Driving the Malignant Transformation of Oral Submucous Fibrosis [Whole transcriptome]

ABSTRACT: OSF is a chronic, progressive, fibrotic condition of the oral mucosa that carries an elevated risk of undergoing malignant transformation. We aimed to identify and validate novel genes associated with the regulation of epithelial to mesenchymal transition (EMT) in Oral submucous fibrosis (OSF). Genes regulating EMT were identified through differential gene expression analysis, with a LogFC threshold of -1 and +1, and padj value < 0.05, utilizing data retrieved from GEO datasets, TCGA-HNSC dataset and whole transcriptome data generated from tissue samples of OSF, OSFSCC (OSF associated with OSCC) and OSCC (Oral squamous cell carcinoma). The curated EMT genes were correlated with functional states of cancer, subjected to clustering to identify the candidate genes. The EMT genes, namely MMP9, SPARC and ITGA5 were identified to be the novel candidate genes. Comprehensive pathway analysis and immunohistochemical analysis confirmed their role in regulating EMT in OSF, OSCC, and OSFSCC. Integration of bioinformatics and proteomics led to the discovery of novel candidate genes regulating EMT. The significant role of candidate genes MMP9, SPARC, and ITGA5 observed in fibrosis and malignancy indicates a novel mechanism of transition from fibrosis associated type 2 EMT to type 3 EMT, driving OSF to malignancy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274203 | GEO | 2025/01/30

REPOSITORIES: GEO

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Project description:Background: Oral submucous fibrosis (OSF) is a precancerous lesion characterized by fibrous tissue deposition, the incidence of which correlates positively with the frequency of betel nut chewing. Prolonged betel nut chewing can damage the integrity of the oral mucosal epithelium, leading to chronic inflammation and local immunological derangement. However, currently, the underlying cellular events driving fibrogenesis and dysfunction are incompletely understood, such that OSF has few treatment options with limited therapeutic effectiveness. Dental pulp stem cells (DPSCs) have been recognized for their anti-inflammatory and anti-fibrosis capabilities, making them promising candidates to treat a range of immune, inflammatory, and fibrotic diseases. However, the application of DPSCs in OSF is inconclusive. Therefore, this study aimed to explore the pathogenic mechanism of OSF and, based on this, to explore new treatment options. Methods: A human cell atlas of oral mucosal tissues was compiled using single-cell RNA sequencing to delve into the underlying mechanisms. Epithelial cells were reclustered to observe the heterogeneity of OSF epithelial cells and their communication with immune cells. The results were validated in vitro, in clinicopathological sections, and in animal models. In vivo, the therapeutic effect and mechanism of DPSCs were characterized by histological staining, immunohistochemical staining, scanning electron microscopy, and atomic force microscopy. Results: A unique epithelial cell population, Epi1.2, with proinflammatory and profibrotic functions, was predominantly found in OSF. Epi1.2 cells also induced the fibrotic process in fibroblasts by interacting with T cells through receptor-ligand crosstalk between macrophage migration inhibitory factor (MIF)-CD74 and C-X-C motif chemokine receptor 4 (CXCR4). Furthermore, we developed OSF animal models and simulated the clinical local injection process in the rat buccal mucosa using DPSCs to assess their therapeutic impact and mechanism. In the OSF rat model, DPSCs demonstrated superior therapeutic effects compared with the positive control (glucocorticoids), including reducing collagen deposition and promoting blood vessel regeneration. DPSCs mediated immune homeostasis primarily by regulating the numbers of KRT19+MIF+ epithelial cells and via epithelial-stromal crosstalk. Conclusions: Given the current ambiguity surrounding the cause of OSF and the limited treatment options available, our study reveals that epithelial cells and their crosstalk with T cells play an important role in the mechanism of OSF and suggests the therapeutic promise of DPSCs.

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Novel Transcripts of EMT Driving the Malignant Transformation of Oral Submucous Fibrosis [Whole transcriptome]

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