Molecular Insights into Oral Squamous Cell Carcinoma: An Interplay of Genetic Mutations and Epigenetic Modifications

Head and neck cancers comprise a diverse range of malignancies, including oral squamous cell carcinoma (OSCC) being the most prevalent, over ۹۰% of oral cavity cases. In ۲۰۲۰, there were ۳۷۷,۷۱۳ cases of OSCC worldwide, and projections indicate ۴۰% an increase of incidence by ۲۰۴۰, with rising in mortality rate. This cancer predominantly affects individuals over ۴۰ years old, with a higher incidence in men due to risk factors such as tobacco use and alcohol consumption, and human papillomavirus (HPV) infection. Despite advances in treatment modalities such as surgery, chemotherapy, and radiotherapy, OSCC remains a highly lethal disease, often diagnosed at advanced stages with lymph node metastasis. The development of OSCC arises from a complex interplay of genetic and epigenetic factors influenced by environmental risk factors. We aim to elucidate the roles of genetic and epigenetic factors in the pathogenesis and progression of OSCC. The pathogenesis of OSCC is driven by complex genetic alterations, including mutations in crucial tumor suppressor genes (e.g., TP۵۳, RB۱, CDKN۲A), which are essential in regulating cell cycle progression and maintaining genomic stability. Furthermore, activation of oncogenes (e.g., EGFR, RAS) contributes to uncontrolled cellular proliferation and tumor growth. Cells in the oral region are constantly exposed to DNA-damaging agents from both internal and external sources. Defects in DNA repair mechanisms, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), double-strand break repair (DSBR), and direct reversion repair (DRR) are critical in the pathogenesis of OSCC. Alterations in key proteins such as p۵۳, BRCA۱, and XRCC۱, along with epigenetic modifications like MLH۱ promoter hypermethylation, contribute to genomic instability and cancer progression. These disruptions underscore the potential of DNA repair markers as prognostic indicators in OSCC. Moreover, the progression of OSCC involves the dysregulation of several critical signaling pathways, including PTEN/PI۳K/AKT/mTOR, Notch, JAK/STAT, and NF-κB. These pathways contribute to tumorigenesis by promoting cell survival, proliferation, immune evasion, and metastasis, while also playing significant roles in chemotherapy and radiotherapy resistance. In depth understanding of these signaling mechanisms is essential for developing more effective targeted therapies and improving clinical outcomes in OSCC. In addition to genetic alterations, this review explores the role of epigenetic modifications in OSCC. Epigenetic changes, such as DNA methylation, histone modifications, and microRNA (miRNA) regulation, are critical in modulating gene expression without altering the underlying DNA sequence. These epigenetic mechanisms could lead to the silencing of tumor suppressor genes or the activation of oncogenes, further promoting carcinogenesis. For instance, hypermethylation of promoter regions in tumor suppressor genes result in their inactivation, while histone modifications alter chromatin structure, affecting gene accessibility and transcription. miRNAs, small non-coding RNAs, regulate gene expression post-transcriptionally, playing roles in both oncogenic and tumor-suppressive pathways. In conclusion, understanding the genetic alterations, signaling pathways, and epigenetic modifications in OSCC is essential for improving clinical management and developing novel therapeutic strategies. This review aims to provide valuable insights into the molecular mechanisms driving OSCC, shedding light on future research and clinical practice.

کلیدواژه ها:

Oral Squamous Cell Carcinoma (OSCC) ، Genetic Alterations ، Epigenetic Modifications ، Tumor Suppressor Genes ، Oncogenes