The Circular RNA circSKA3 Binds Integrin β1 to Induce Invadopodium Formation Enhancing Breast Cancer Invasion
The Circular RNA circSKA3 Binds Integrin β1 to Induce Invadopodium Formation Enhancing Breast Cancer Invasion
复制标题
DOI：
10.1016/j.ymthe.2020.03.002
复制
发表时间：
2020-05-06
影响因子：
12.4
通讯作者：
Yang, Burton B.
中科院分区：
文献类型：
--
作者：
Du, William W.;Yang, Weining;Yang, Burton B.
转移性癌细胞通过形成动态肌动蛋白基侵袭伪足侵入周围组织，其降解周围细胞外基质并允许癌细胞侵入。调控RNA，包括环状RNA，已经涉及到这个过程。通过基因芯片技术，我们发现环状RNA circSKA 3在乳腺癌细胞和人乳腺癌组织中高表达。我们进一步发现，乳腺癌细胞的侵袭能力与circSKA 3表达正相关，通过形成侵袭伪足。从机制上讲，我们确定Tks 5和整合素β 1作为这些肿瘤来源的侵袭伪足中的circSKA 3结合伴侣。在体外和体内，异位circSKA 3表达赋予增加的肿瘤侵袭力。我们进一步鉴定了circSKA 3、Tks 5和整合素β 1之间的RNA-蛋白结合位点。在肿瘤形成测定中，我们发现circSKA 3表达促进肿瘤进展和侵袭足形成。circSKA 3结合位点的突变或用阻断寡核苷酸转染消除了观察到的效果。因此，我们提供的证据表明，环状RNA circSKA 3通过与Tks 5和整合素β 1复合，诱导侵袭性伪足形成，促进肿瘤进展。
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 beta 1 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 beta 1. 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 beta 1, inducing invadopodium formation.