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首页> 外文期刊>Molecular cancer research: MCR >KIF3a Promotes Proliferation and Invasion via Wnt Signaling in Advanced Prostate Cancer
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KIF3a Promotes Proliferation and Invasion via Wnt Signaling in Advanced Prostate Cancer

机译：KIF3a通过Wnt信号促进晚期前列腺癌的增殖和侵袭

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摘要

Aberrant activation of the Wnt/beta-catenin signaling pathway is a critical event in advanced prostate cancer, but the genetic alterations that 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 upregulated in the majority of human prostate cancer cell lines and primary tumor biopsies. The expression levels of KIF3a correlate with a higher Gleason score, tumor-node-metastasis stage, 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 beta-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 upregulation of KIF3a is causal of aberrant activation of Wnt signaling in advanced prostate cancer through the KIF3a-DVL2-beta-catenin axis.
机译：Wnt /β-catenin信号通路的异常激活是晚期前列腺癌的关键事件，但是在许多其他癌症中，激活Wnt信号通路的遗传改变在前列腺癌中很少观察到。调节前列腺癌中Wnt信号通路的其他分子机制仍有待确定。在此，证明了KIF3a是驱动蛋白II运动蛋白的亚基，在前列腺癌中作为Wnt信号通路的激动剂起作用。在大多数人前列腺癌细胞系和原发性肿瘤活检物中，KIF3a上调。 KIF3a的表达水平与更高的格里森评分，肿瘤淋巴结转移阶段和前列腺癌的转移状态相关。此外，KIF3a的外源表达促进良性前列腺细胞中的细胞生长，而使癌细胞中的KIF3a沉默会降低细胞增殖，不依赖锚定的细胞生长以及细胞迁移/侵袭。从机制上讲，KIF3a增加了前列腺癌细胞中CK1依赖的DVL2磷酸化和β-连环蛋白的活化，从而导致Wnt信号靶基因如细胞周期蛋白D1，HEF1和MMP9的反式激活。这些发现支持以下观点：KIF3a的上调是通过KIF3a-DVL2-β-catenin轴导致晚期前列腺癌Wnt信号异常激活的原因。

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