Low-dose ionizing radiation drives thyroid carcinogenesis via VPS53 enhanced EGFR Re-recycling.

Ionizing radiation is a confirmed independent environmental factor for thyroid cancer. Environmental and occupational exposure are exposed to low-dose ionizing radiation (LDR), which underscores the persistent need to decipher the mechanisms of LDR induced thyroid carcinogenesis. In addition to the canonical driver mutations or chromosomal rearrangements, there remains a gap in understanding the key drivers of LDR-induced thyroid cancer that needs to be clarified. VPS53, a core subunit of the Golgi-associated retrograde protein (GARP) complex, mediates retrograde vesicular trafficking, but its role in LDR-induced thyroid tumorigenesis is uncharacterized. Here, we found that LDR induces an increase in VPS53 copy number in clones of thyroid follicular epithelial cell malignant transformation, leading to elevated expression levels, and high VPS53 expression is associated with poor prognosis in thyroid cancer patients. Functionally, VPS53 promotes the proliferation and clonal formation of thyroid cancer cells; meanwhile, xenograft tumor experiments in nude mice demonstrated that high expression of VPS53 facilitates tumor growth. Mechanistically, VPS53 directly interacts with EGFR, redirecting it from the lysosomal degradation pathway to the plasma membrane recycling pathway, thereby maintaining the sustained activation of the carcinogenesis signaling pathway. Moreover, VPS53 alters the direction of DNA double-strand break repair, favoring non-homologous end joining (NHEJ) over homologous recombination (HR), which exacerbates genomic instability. These mechanisms collectively promote the thyroid carcinogenesis. Collectively, we have confirmed a novel mechanism by which the VPS53-EGFR axis drives thyroid carcinogenesis induced by LDR, and provided new insights into thyroid tumor biology.