The miR-302 family suppresses tumor growth in tongue squamous cell carcinoma by directly targeting P65.

Tongue squamous cell carcinoma (TSCC) is an aggressive malignancy with a poor prognosis. The miR-302 family of microRNAs regulates stemness and differentiation, but its role in TSCC remains unknown. Here, we report that miR-372-3p, miR-302c-3p, and miR-520a-3p function as potent tumor suppressors in TSCC. These miRNAs inhibited cell proliferation, clonogenic growth, and induced apoptosis in vitro and in vivo. Transcriptomic analysis revealed that miR-302 overexpression silences pro-survival and inflammatory pathways. We found that these miRNAs directly target the NF-κB subunit P65 (RELA), which is upregulated in TSCC. Knockdown of P65 recapitulated the tumor-suppressive effects of miR-302, whereas P65 reconstitution partially rescued apoptosis and growth inhibition caused by miR-302. Both P65 knockdown and miR-302 overexpression dramatically slowed tumor growth in vivo. Our results demonstrate the therapeutic potential of a novel miR-302/P65 axis that limited the progression of TSCC by regulating apoptosis and oncogenic transcription.