PDF(Pubmed)
Abstract：
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.
摘要：
众所周知,异常可变剪接与各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仍未被研究.这里,我们发现,与原发灶相比,RBM7在乳腺癌淋巴结和远处器官转移中的表达降低,且RBM7的低表达与乳腺癌患者的无病生存率降低相关.与扰乱对照细胞相比，具有RBM7消耗的乳腺癌细胞显示出增加的肺转移潜力。RBM7的缺失刺激了乳腺癌细胞的迁移，入侵,和血管生成。机械上,RBM7控制MFGE8的拼接开关，有利于生产MFGE8的主要同种型，MFGE8-L。这导致STAT1磷酸化的减弱和细胞粘附分子的改变。MFGE8-L对乳腺癌细胞的迁移和侵袭能力具有抑制作用，而截断的同种型MFGE8-S，缺乏第二个F5/8型C结构域具有相反的效果。此外,RBM7负调节NF-κB级联,并且NF-κB抑制剂可阻碍由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包涵体之间呈正相关，为分子靶向治疗乳腺癌提供新的机制见解。
