
RBM7 の欠損は、MFGE8 のスプライシング変化と NF-κB 経路の活性化を通して、乳がんの転移能を促進する。


coremsg

Aberrant alternative splicing is well-known to be closely associated with tumorigenesis of various cancers. However, the intricate mechanisms underlying breast cancer metastasis driven by deregulated splicing events remain largely unexplored. Here, we unveiled RBM7 as a novel regulator of alternative splicing that plays a crucial role in counteracting the metastatic potential of breast cancer. Through bioinformatics analysis and IHC staining validation, we revealed that RNA binding motif protein 7 (RBM7) is decreased in lymph node and distant organ metastases of breast cancer as compared to primary lesions. Furthermore, we found that low expression of RBM7 is correlated with the reduced disease-free survival of breast cancer patients. Breast cancer cells with RBM7 depletion exhibited an increased potential for lung metastasis compared to scramble control cells. The absence of RBM7 stimulated breast cancer cell migration, invasion, and angiogenesis. Mechanistically, RBM7 controlled the splicing switch of MFGE8, favoring the production of the predominant isoform of MFGE8, MFGE8-L. This resulted in the attenuation of STAT1 phosphorylation and alterations in cell adhesion molecules. MFGE8-L exerted an inhibitory effect on the migratory and invasive capability of breast cancer cells, while the truncated isoform MFGE8-S, which lack the second F5/8 type C domain had the opposite effect. Particularly, the ectopic expression of MFGE8-L significantly reversed the pro-invasion effect of RBM7 silencing, but did not contribute to the promotion of angiogenesis-related secreted proteins. In RBM7-depleted cells, a gene set enrichment analysis revealed a significant amplification of the NF-κB cascade. Concordantly, RBM7 negatively regulates p65 phosphorylation. Furthermore, an NF-κB inhibitor could obstruct the increase in HUVEC tube formation caused by RBM7 silencing. Clinically, we noticed a positive correlation between RBM7 expression and MFGE8 exon7 inclusion in breast cancer tissues. Therefore, our study not only offer mechanistic insights into how abnormal splicing contributes to the aggressiveness of breast cancer, but also provide a new approach for molecular-targeted therapy in combating breast cancer.

### Competing Interest Statement

The authors have declared no competing interest.

RBM7 deficiency promotes breast cancer metastasis by coordinating MFGE8 splicing switch and NF-kB pathway

乳がん転移を促進する-rbm7-欠損の機序-mfge8-スプライシング変化と-nf-κb-経路の協調的制御


乳がん転移を促進する RBM7 欠損の機序 - MFGE8 スプライシング変化と NF-κB 経路の協調的制御
