Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia.
Flinders Centre for Innovation in Cancer, College of Medicine & Public Health, Flinders University, Adelaide, SA, Australia.
EMBO J. 2018 Jul 2;37(13). doi: 10.15252/embj.201899016. Epub 2018 Jun 5.
Members of the miR-200 family are critical gatekeepers of the epithelial state, restraining expression of pro-mesenchymal genes that drive epithelial-mesenchymal transition (EMT) and contribute to metastatic cancer progression. Here, we show that miR-200c and another epithelial-enriched miRNA, miR-375, exert widespread control of alternative splicing in cancer cells by suppressing the RNA-binding protein Quaking (QKI). During EMT, QKI-5 directly binds to and regulates hundreds of alternative splicing targets and exerts pleiotropic effects, such as increasing cell migration and invasion and restraining tumour growth, without appreciably affecting mRNA levels. QKI-5 is both necessary and sufficient to direct EMT-associated alternative splicing changes, and this splicing signature is broadly conserved across many epithelial-derived cancer types. Importantly, several actin cytoskeleton-associated genes are directly targeted by both QKI and miR-200c, revealing coordinated control of alternative splicing and mRNA abundance during EMT These findings demonstrate the existence of a miR-200/miR-375/QKI axis that impacts cancer-associated epithelial cell plasticity through widespread control of alternative splicing.
miR-200 家族成员是上皮状态的关键调控因子，它们抑制促进上皮-间充质转化（EMT）的促间充质基因的表达，促进转移性癌症的进展。在这里，我们表明 miR-200c 和另一种上皮细胞丰富的 miRNA，miR-375，通过抑制 RNA 结合蛋白 Quaking (QKI) 对癌细胞中的选择性剪接进行广泛的控制。在 EMT 过程中，QKI-5 直接结合并调节数百个选择性剪接靶标，并发挥多效性作用，如增加细胞迁移和侵袭，抑制肿瘤生长，而不会明显影响 mRNA 水平。QKI-5 是 EMT 相关的选择性剪接变化所必需和充分的，这种剪接特征在许多上皮源性癌症类型中广泛保守。重要的是，几个肌动蛋白细胞骨架相关基因是 QKI 和 miR-200c 的直接靶点，揭示了 EMT 过程中选择性剪接和 mRNA 丰度的协调控制。这些发现表明存在一个 miR-200/miR-375/QKI 轴，通过广泛控制选择性剪接来影响与癌症相关的上皮细胞可塑性。
