Sino-US Research Center for Cancer Translational Medicine of the Second Affiliated Hospital of Dalian Medical University & Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Department of Oncology & Sino-US Research Center for Cancer Translational Medicine, the Second Affiliated Hospital, Dalian Medical University, Dalian, China.
Elife. 2024 Jul 12;13:RP95318. doi: 10.7554/eLife.95318.
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.
异常的选择性剪接与各种癌症的肿瘤发生密切相关。然而，调控剪接事件驱动的乳腺癌转移的复杂机制在很大程度上仍未得到探索。在这里，我们揭示了与原发性病变相比，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无病生存率降低相关。与 scramble 对照细胞相比，RBM7 耗竭的乳腺癌细胞表现出增加的肺转移潜力。RBM7 的缺失刺激了乳腺癌细胞的迁移、侵袭和血管生成。在机制上，RBM7 控制 MFGE8 的剪接开关，有利于 MFGE8 的主要异构体 MFGE8-L 的产生。这导致 STAT1 磷酸化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发挥抑制作用，而缺乏第二个 F5/8 型 C 结构域的截短异构体 MFGE8-S 则具有相反的作用。此外，RBM7 负调控 NF-κB 级联反应，NF-κB 抑制剂可以阻止 RBM7 沉默引起的 HUVEC 管形成增加。临床上，我们注意到 RBM7 表达与乳腺癌组织中 MFGE8 外显子 7 包含之间存在正相关，为针对乳腺癌的分子靶向治疗提供了新的机制见解。
