Bijnsdorp Irene V, Hodzic Jasmina, Lagerweij Tonny, Westerman Bart, Krijgsman Oscar, Broeke Jurjen, Verweij Frederik, Nilsson R Jonas A, Rozendaal Lawrence, van Beusechem Victor W, van Moorselaar Jeroen A, Wurdinger Thomas, Geldof Albert A
Department of Urology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Oncotarget. 2016 Mar 29;7(13):16676-87. doi: 10.18632/oncotarget.7572.
The centrosome plays a key role in cancer invasion and metastasis. However, it is unclear how abnormal centrosome numbers are regulated when prostate cancer (PCa) cells become metastatic. CP110 was previously described for its contribution of centrosome amplification (CA) and early development of aggressive cell behaviour. However its regulation in metastatic cells remains unclear. Here we identified miR-129-3p as a novel metastatic microRNA. CP110 was identified as its target protein. In PCa cells that have metastatic capacity, CP110 expression was repressed by miR-129-3p. High miR-129-3p expression levels increased cell invasion, while increasing CP110 levels decreased cell invasion. Overexpression of CP110 in metastatic PCa cells resulted in a decrease in the number of metastasis. In tissues of PCa patients, low CP110 and high miR-129-3p expression levels correlated with metastasis, but not with the expression of genes related to EMT. Furthermore, overexpression of CP110 in metastatic PCa cells resulted in excessive-CA (E-CA), and a change in F-actin distribution which is in agreement with their reduced metastatic capacity. Our data demonstrate that miR-129-3p functions as a CA gatekeeper in metastatic PCa cells by maintaining pro-metastatic centrosome amplification (CA) and preventing anti-metastatic E-CA.
中心体在癌症侵袭和转移中起关键作用。然而，尚不清楚前列腺癌细胞发生转移时异常的中心体数量是如何被调控的。CP110此前被描述为在中心体扩增（CA）及侵袭性细胞行为早期发展中发挥作用。然而其在转移细胞中的调控机制仍不清楚。在此，我们鉴定出miR-129-3p是一种新型的转移相关微小RNA。CP110被确定为其靶蛋白。在具有转移能力的前列腺癌细胞中，CP110的表达受到miR-129-3p的抑制。高表达的miR-129-3p水平增加细胞侵袭能力，而增加CP110水平则降低细胞侵袭能力。在转移性前列腺癌细胞中过表达CP110导致转移数量减少。在前列腺癌患者组织中，低水平的CP110和高水平的miR-129-3p表达与转移相关，但与上皮-间质转化相关基因的表达无关。此外，在转移性前列腺癌细胞中过表达CP110导致过度中心体扩增（E-CA），以及F-肌动蛋白分布改变，这与其降低的转移能力一致。我们的数据表明，miR-129-3p通过维持促转移的中心体扩增（CA）并防止抗转移的E-CA，在转移性前列腺癌细胞中作为中心体扩增的守门人发挥作用。
