METTL3/IGF2BP1/CD47 contributes to the sublethal heat treatment induced mesenchymal transition in HCC

Microwave ablation is a first-line treatment of small hepatocellular carcinoma (HCC), while incomplete ablation induces recurrence and metastasis. However, its underlying mechanism remains largely unexplored. Here we reported that sublethal heat treatment (46 °C) strongly promoted migration and EMT transition in HCC cells. Mechanistic investigation revealed that compared with 37 °C, HCC cells treated with 46 °C expressed higher level of CD47. Knockdown of CD47 significantly attenuated sublethal heat treatment stimulated migration and EMT transition. In addition, METTL3 which is the key enzyme of m⁶A modification was also induced by 46 °C treatment and triggered CD47 expression in HCC cells. Moreover, CD47 mRNA degradation was further proved to be stabled in the IGF2BP1-dependent manner. Importantly, sublethal heat treatment stimulated CD47 expression and EMT transition were also confirmed in patient-derived organoid. Taken together, our study suggests that METTL3/IGF2BP1/CD47 mediated EMT transition contributes to the incomplete ablation induced metastasis in HCC cells. Moreover, these findings identify the METTL3/IGF2BP1/CD47 axis as a potential therapeutic target for the microwave ablation and shed new lights on the crosstalk between incomplete heat ablation and RNA methylation.