A mechanism diagram of IGF2BP3 promoting progression of HNSCC by stabilizing circHECTD2 in an m⁶A modification-dependent manner. Data are presented as mean ± SD, *p < 0.05, **p < 0.01, ns, not significant, using a student's test. [Photo/Shandong University]

A research team led by Professor Lei Dapeng from Qilu Hospital of Shandong University (SDU) has uncovered a molecular mechanism driving the progression of head and neck squamous cell carcinoma (HNSCC). Published in the journal Molecular Cancer, the study delineates how an m⁶A-dependent regulatory axis facilitates tumor malignancy, offering promising new biomarkers and therapeutic targets for this aggressive disease.

HNSCC remains the seventh-most-common cancer worldwide, notorious for its high invasiveness, frequent metastasis, and poor prognosis. Despite the cancer's prevalence, the clinical landscape suffers from a lack of effective early diagnostic markers and targeted therapies. The SDU team addressed this challenge by investigating N6-methyladenosine (m⁶A) modification, a common RNA epigenetic finish whose role in circular RNAs (circRNAs) within HNSCC has long remained elusive.

The findings reveal that the m⁶A reader protein IGF2BP3 is significantly overexpressed in HNSCC patients, correlating with poor clinical outcomes. Mechanistically, IGF2BP3 binds to and stabilizes circHECTD2 through m⁶A modification. Once stabilized, circHECTD2 acts as a "molecular sponge", sequestering specific microRNAs to prevent the degradation of SMAD2 mRNA. This chain reaction ultimately fuels the proliferation and spread of cancer cells.

By mapping the complete IGF2BP3/circHECTD2/SMAD2 signaling pathway, the study provides a breakthrough in understanding HNSCC pathogenesis. These insights not only facilitate more accurate prognostic stratification but also pave the way for developing innovative targeted drugs, potentially improving survival rates for patients battling this refractory disease.