ASC modulates HIF-1α stability and induces cell mobility in OSCC

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis Research

Background:

• High expression of Apoptosis-associated speck-like protein containing a CARD (ASC) is linked to lymph node metastasis in oral squamous cell carcinoma (OSCC).
• The precise molecular mechanisms driving ASC-induced metastasis in OSCC remain largely undefined.

Purpose of the Study:

• To elucidate the underlying mechanism by which ASC promotes metastasis in OSCC.
• To investigate the potential role of Hypoxia-inducible factor 1-alpha (HIF-1α) in ASC-mediated OSCC metastasis.

Main Methods:

• Gene expression analysis (RNA-seq) of ASC-overexpressed OSCC cells and patient datasets (OSCC-Taiwan, OSCC-TCGA).
• Identification of ASC-induced, cell-motion-associated genes and analysis of their promoter regions for HIF-1α binding motifs.
• Assessment of ASC-HIF-1α interaction, stabilization, and downstream effects on HIF-1α pathway molecules.
• Evaluation of OSCC cell migration and invasion following HIF-1α inhibition.

Main Results:

• 195 cell-motion-associated genes were identified; 14 were significantly overexpressed in OSCC tissues, with 9 validated in TCGA samples.
• RRAS2, PDGFA, and VEGFA, among the upregulated genes, correlated with poorer patient survival in OSCC.
• ASC directly interacts with and stabilizes HIF-1α under normoxia, decreasing HIF-1α ubiquitination and hydroxylation.
• Inhibition of HIF-1α synthesis significantly reduced the migration and invasion capabilities of ASC-overexpressing OSCC cells.

Conclusions:

• A novel regulatory pathway involving ASC and HIF-1α is identified as a key contributor to lymph node metastasis in OSCC.
• This ASC-HIF-1α axis represents a potential therapeutic target for improving treatment strategies in OSCC.