Metastatic cancer cells invade surrounding tissues by forming dynamic actin-based invadopodia, which degrade the surrounding extracellular matrix and allow cancer cell invasion. Regulatory RNAs, including circular RNA, have been implicated in this process. By microarray, we found that the circular RNA circSKA3 was highly expressed in breast cancer cells and human breast cancer tissues. We further found that the invasive capacity of breast cancer cells was positively correlated with circSKA3 expression, through the formation of invadopodia. Mechanistically, we identified Tks5 and integrin β1 as circSKA3 binding partners in these tumor-derived invadopodia. Ectopic circSKA3 expression conferred increased tumor invasiveness in vitro and in vivo. We further identified the RNA-protein binding sites between circSKA3, Tks5 and integrin β1. In tumor formation assays, we found that circSKA3 expression promoted tumor progression and invadopodium formation. Mutation of the circSKA3 binding sites or transfection with blocking oligos abrogated the observed effects. Thus, we provide evidence that the circular RNA circSKA3 promotes tumor progression by complexing with Tks5 and integrin β1, inducing invadopodium formation.

中文翻译：

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环状RNA circSKA3与整联蛋白β1结合，诱导侵袭性载禽上皮形成，增强了乳腺癌的侵袭能力。

转移性癌细胞通过形成动态的基于肌动蛋白的侵袭伪足侵袭周围组织，从而破坏周围的细胞外基质并允许癌细胞侵袭。调控RNA，包括环状RNA，已经牵涉到该过程中。通过微阵列，我们发现环状RNA circSKA3在乳腺癌细胞和人类乳腺癌组织中高表达。我们进一步发现，通过侵袭伪足的形成，乳腺癌细胞的侵袭能力与circSKA3表达正相关。从机制上讲，我们将Tks5和整联蛋白β1鉴定为这些肿瘤来源的伪足动物中circSKA3的结合伴侣。异位circSKA3表达赋予体外和体内肿瘤侵袭性增加。我们进一步鉴定了circSKA3，Tks5和整联蛋白β1之间的RNA蛋白结合位点。在肿瘤形成试验中，我们发现circSKA3表达促进了肿瘤的进展和invadopodium的形成。circSKA3结合位点的突变或封闭寡核苷酸的转染废除了观察到的效果。因此，我们提供了证据，即环状RNA circSKA3通过与Tks5和整联蛋白β1结合，促进了invadopodium的形成，促进了肿瘤的进展。