Tumor volume increases continuously in the advanced stage, and aside from the self-renewal of tumor cells, whether the oncogenic transformation of surrounding normal cells is involved in this process is currently unclear. Here, we show that oral squamous cell carcinoma (OSCC)-derived small extracellular vesicles (sEVs) promote the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of normal epithelial cells but delay their apoptosis. In addition, nuclear-cytoplasmic invaginations and multiple nucleoli are observed in sEV-treated normal cells, both of which are typical characteristics of premalignant lesions of OSCC. Mechanistically, miR-let-7c in OSCC-derived sEVs is transferred to normal epithelial cells, leading to the transcriptional inhibition of p53 and inactivation of the p53/PTEN pathway. In summary, we demonstrate that OSCC-derived sEVs promote the precancerous transformation of normal epithelial cells, in which the miR-let-7c/p53/PTEN pathway plays an important role. Our findings reveal that cancer cells can corrupt normal epithelial cells through sEVs, which provides new insight into the progression of OSCC.

晚期肿瘤体积不断增大，除了肿瘤细胞的自我更新外，这一过程是否涉及周围正常细胞的致癌转化目前尚不清楚。在这里，我们展示了口腔鳞状细胞癌 (OSCC) 衍生的小细胞外囊泡 (sEV) 促进了正常上皮细胞的增殖、迁移、侵袭和上皮间质转化 (EMT)，但延迟了它们的凋亡。此外，在sEV处理的正常细胞中观察到核质内陷和多个核仁，这两者都是OSCC癌前病变的典型特征。从机制上讲，OSCC 衍生的 sEV 中的 miR-let-7c 被转移到正常上皮细胞，导致 p53 的转录抑制和 p53/PTEN 通路的失活。总之，我们证明了 OSCC 衍生的 sEV 促进了正常上皮细胞的癌前转化，其中 miR-let-7c/p53/PTEN 通路发挥了重要作用。我们的研究结果表明，癌细胞可以通过 sEV 破坏正常的上皮细胞，这为 OSCC 的进展提供了新的见解。