IGF2BP3 promotes autophagy-mediated TNBC metastasis via m6A-dependent, cap-independent c-Met translation

Metastatic tumors pose clinical treatment challenges due to their high adaptability to diverse environments. The cooperation of epigenetic modifications and metabolic adaptations enables tumor cells to dynamically adjust for survival in variable environments, which is crucial for tumor metastasis and worth exploring in depth.

RNA immunoprecipitation sequencing, transmission electron microscopy photograph and GFP-mCherry-LC3 fluorescence imaging were employed to reveal the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) in triple-negative breast cancer (TNBC) cells. Then, in the presence of rapamycin, further experiments showed that IGF2BP3's role in TNBC metastasis was autophagy-mediated. Methylated RNA immunoprecipitation sequencing, luciferase assays and co-immunoprecipitation mass spectrometry showed that IGF2BP3 promoted mRNA translation initiation in an N6-methyladenosine (m6A)-dependent manner.

We found that IGF2BP3 could link epigenetic modification and metabolic adaptation to promote autophagy-mediated TNBC metastasis. As an m6A binding protein that is specifically highly expressed in TNBC, IGF2BP3 could bind to the m6A motif of c-Met mRNA, regulating autophagy-mediated epithelial-to-mesenchymal transition via the c-Met/PI3K/AKT/mTOR pathway. Moreover, IGF2BP3 recruited eIF4G2 as a collaborator, promoting c-Met protein expression by facilitating m6A-dependent and cap-independent mRNA translation initiation, rather than affecting mRNA stability.

Our study expands the understanding of IGF2BP3's role in TNBC metastasis by establishing its function in regulating autophagy. Notably, IGF2BP3 could bind to the m6A motif on the 5' and 3' untranslated regions (UTRs) of c-Met mRNA to facilitate its translation in a cap-independent manner.