Dual Disruption of EGFR/PI3K Signaling: IGF2BP2 Targeting Reverses Anti-EGFR Resistance in CAFs-Infiltrated Oral...

Area of Science:

• Molecular Oncology
• Cancer Genomics
• RNA Biology

Background:

• RNA-binding proteins (RBPs) regulate gene expression but their role in oral squamous cell carcinoma (OSCC) is not well understood.
• Identifying dysregulated RBPs in OSCC is crucial for understanding disease mechanisms and developing targeted therapies.

Purpose of the Study:

• To investigate the role and mechanism of RNA-binding proteins (RBPs), specifically IGF2BP2, in oral squamous cell carcinoma (OSCC) progression.
• To evaluate IGF2BP2 as a potential therapeutic target for OSCC, including overcoming resistance to existing treatments.

Main Methods:

• Integrated analysis of RNA-seq and single-cell RNA-seq data to identify dysregulated RBPs in OSCC.
• Functional evaluation of IGF2BP2 using cell-based assays, xenograft models, and Igf2bp2-deficient mice.
• Mechanistic studies involving RNA-seq, RIP-seq, RIP/MeRIP-qPCR, and luciferase assays to identify IGF2BP2 targets and pathways.
• In vitro and in vivo validation of an IGF2BP2 inhibitor for therapeutic efficacy.

Main Results:

• IGF2BP2 was identified as the most upregulated RBP in OSCC cells and cancer-associated fibroblasts (CAFs), correlating with poor prognosis.
• IGF2BP2 depletion inhibited OSCC proliferation and metastasis, and delayed tongue SCC onset in mouse models.
• IGF2BP2 stabilizes EGFR and PIK3R1 mRNA via m6A-dependent interactions, activating the EGFR/PI3K/AKT pathway.
• IGF2BP2 inhibition demonstrated anti-OSCC efficacy by suppressing EGFR and PI3K/AKT activity, overcoming resistance mechanisms.

Conclusions:

• IGF2BP2 is a key regulator of OSCC progression and a promising therapeutic target.
• Targeting IGF2BP2 offers a novel strategy for OSCC treatment, particularly for patients with resistance to anti-EGFR therapy.
• The findings elucidate a critical RBP-mediated oncogenic axis in OSCC, paving the way for new therapeutic interventions.