Hypoxia-regulated non-coding RNAs in OSCC liquid biopsy: from molecular mechanisms to AI-driven precision oncology
Abstract
Background: Oral squamous cell carcinoma (OSCC) is characterized by late-stage diagnosis and high recurrence rates. Intratumoral hypoxia, driven by hypoxia-inducible factors 1α and 2α (HIF-1α/HIF-2α), orchestrates aggressive phenotypes including epithelial-mesenchymal transition (EMT), metabolic reprogramming, stemness maintenance, and therapeutic resistance. Non-coding RNAs (ncRNAs) serve as central post-transcriptional regulators of these hypoxic adaptations and offer promising non-invasive biomarker potential.
Methods: A systematic literature search of the PubMed database was executed on May 15, 2026, using structured Boolean combinations of Medical Subject Headings (MeSH) terms and high-accuracy text keywords targeting OSCC, hypoxia pathways (HIF-1α/HIF-2α), non-coding RNA classes (miRNAs, lncRNAs, circRNAs), and liquid biopsy media (saliva, plasma, serum, exosomes).
Results: Hypoxic stress stabilizes HIF-1α during acute oxygen deprivation and HIF-2α during chronic adaptation, driving widespread dysregulation across the non-coding transcriptome. HIF-1α-activated "hypoxemirs" (e.g., miR-210) and oncogenic lncRNAs (MALAT1, H19, HOTAIR) coordinate early glycolytic switching and invasive EMT cascades. Conversely, chronic HIF-2α activation regulates specific downstream targets (e.g., lncRNA RAB11B-AS1, NEAT1) linked to persistent microvascular remodeling and cancer stem cell preservation. Closed-loop circular RNAs (e.g., circCDR1as, hsa-circ-0001030) display enhanced…
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