KIF3a promotes proliferation and invasion via Wnt signaling in advanced prostate cancer.
KIF3a promotes proliferation and invasion via Wnt signaling in advanced prostate cancer.
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DOI：
10.1158/1541-7786.mcr-13-0418
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Liu W
中科院分区：
文献类型：
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作者：
Liu Z;Rebowe RE;Wang Z;Li Y;Wang Z;DePaolo JS;Guo J;Qian C;Liu W
Wnt/β-catenin信号通路的异常激活是晚期前列腺癌的关键事件，但在许多其他癌症中激活Wnt信号通路的遗传改变在前列腺癌中很少观察到。前列腺癌中调节Wnt信号通路的其他分子机制仍有待确定。本研究表明，KIF3a是运动蛋白激酶ii的一个亚基，在前列腺癌中作为Wnt信号通路的激动剂起作用。KIF3a在大多数人类前列腺癌细胞系和原发肿瘤活检中上调。KIF3a的表达水平与较高的Gleason评分、TNM分级和前列腺癌转移状态相关。此外，外源表达KIF3a促进了良性前列腺细胞的细胞生长，而在癌细胞中沉默KIF3a会降低细胞增殖、不依赖于锚定的细胞生长和细胞迁移/侵袭。在机制上，KIF3a增加前列腺癌细胞中ck1依赖性DVL2磷酸化和β-catenin激活，导致Wnt信号靶基因如Cyclin D1、HEF1和MMP9的反激活。这些发现支持了KIF3a上调是通过KIF3a- dvl2 -β-catenin轴导致晚期前列腺癌Wnt信号异常激活的观点。KIF3a的失活可能提高Wnt信号激活的晚期前列腺癌患者的生存率。
Aberrant activation of the Wnt/β-catenin signaling pathway is a critical event in advanced prostate cancer, but the genetic alterations which activate the Wnt signaling pathway in many other cancers are rarely observed in prostate cancer. Other molecular mechanisms that regulate the Wnt signaling pathway in prostate cancer remain to be identified. Here it is demonstrated that KIF3a, a subunit of kinesin-II motor protein, functions as an agonist of the Wnt signaling pathway in prostate cancer. KIF3a is up-regulated in the majority of human prostate cancer cell lines and primary tumor biopsies. The expression levels of KIF3a correlate with a higher Gleason score, TNM grade, and metastatic status of prostate cancer. Moreover, exogenous expression of KIF3a promoted cell growth in the benign prostate cells, whereas silencing KIF3a in cancer cells decreased cell proliferation, anchorage-independent cell growth, and cell migration/invasion. Mechanistically, KIF3a increases CK1-dependent DVL2 phosphorylation and β-catenin activation in prostate cancer cells, leading to transactivation of the Wnt signaling target genes such as Cyclin D1, HEF1, and MMP9. These findings support the notion that up-regulation of KIF3a is causal of aberrant activation of Wnt signaling in advanced prostate cancer through the KIF3a-DVL2-β-catenin axis. Inactivation of KIF3a may improve survival of patients with advanced prostate cancer in which Wnt signaling is activated.