众所周知，异常的选择性剪接与多种癌症的肿瘤发生密切相关。然而，由剪接事件失调驱动的乳腺癌转移的复杂机制在很大程度上仍未被探索。在这里，我们揭示了与原发灶相比，RBM7在乳腺癌的淋巴结和远处器官转移中减少，并且RBM7的低表达与乳腺癌患者的无病生存率降低相关。与乱序对照细胞相比，RBM7 耗尽的乳腺癌细胞表现出更高的肺转移潜力。 RBM7 的缺失会刺激乳腺癌细胞迁移、侵袭和血管生成。从机制上讲，RBM7 控制 MFGE8 的剪接开关，有利于 MFGE8 的主要亚型 MFGE8-L 的产生。这导致 STAT1 磷酸化减弱和细胞粘附分子改变。 MFGE8-L对乳腺癌细胞的迁移和侵袭能力产生抑制作用，而缺乏第二个F5/8 C型结构域的截短亚型MFGE8-S则具有相反的作用。此外，RBM7 负向调节 NF-κB 级联，NF-κB 抑制剂可以阻碍 RBM7 沉默引起的 HUVEC 管形成的增加。临床上，我们注意到乳腺癌组织中 RBM7 表达与 MFGE8 外显子 7 包含之间呈正相关，为对抗乳腺癌的分子靶向治疗提供了新的机制见解。© 2024，Huang，Dai，Yu 等人。

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 that RBM7 is decreased in lymph node and distant organ metastases of breast cancer as compared to primary lesions and 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. In addition, RBM7 negatively regulates the NF-κB cascade and 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, providing new mechanistic insights for molecular-targeted therapy in combating breast cancer.© 2024, Huang, Dai, Yu et al.