α-parvin (PARVA) is known to be involved in the linkage of integrins, regulation of actin cytoskeleton dynamics and cell survival. However, the role that PARVA plays in cancer progression remains unclear. Here, using a lung cancer invasion cell line model and expression microarrays, we identify PARVA as a potential oncogene. The overexpression of PARVA increased cell invasion, colony-forming ability and endothelial cell tube formation. By contrast, knockdown of PARVA inhibited invasion and tube formation in vitro. Overexpression of PARVA also promoted tumorigenicity, angiogenesis and metastasis in in vivo mouse models. To explore the underlying mechanism, we compared the expression microarray profiles of PARVA-overexpressing cells with those of control cells to identify the PARVA-regulated signalling pathways. Pathway analysis showed that eight of the top 10 pathways are involved in invasion, angiogenesis and cell death. Next, to identify the direct downstream signalling pathway of PARVA, 371 significantly PARVA-altered genes were analysed further using a transcription factor target model. Seven of the top 10 PARVA-altered transcription factors shared a common upstream mediator, ILK. Lastly, we found that PARVA forms a complex with SGK1 and ILK to enhance the phosphorylation of ILK, which led to the phosphorylation of Akt and GSK3β. Notably, the inactivation of ILK reversed PARVA-induced invasion. Taken together, our findings imply that PARVA acts as an oncogene by activating ILK, and that this activation is followed by the activation of Akt and inhibition of GSK3β. To our knowledge, this is the first study to characterize the role of PARVA in lung cancer progression.

中文翻译：

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PARVA通过调节ILK信号通路在肺腺癌中促进转移。

已知α-parvin（PARVA）参与整联蛋白的连接，肌动蛋白细胞骨架动力学的调节和细胞存活。但是，PARVA在癌症进展中的作用仍不清楚。在这里，使用肺癌侵袭细胞系模型和表达微阵列，我们确定PARVA为潜在的癌基因。PARVA的过表达增加细胞侵袭，集落形成能力和内皮细胞管形成。相反，敲除PARVA可以抑制体外侵袭和管形成。PARVA的过表达还促进了体内小鼠模型的致瘤性，血管生成和转移。为了探索潜在的机制，我们比较了过表达PARVA的细胞和对照细胞的表达微阵列谱，以鉴定PARVA调节的信号通路。途径分析表明，前10种途径中有8种与侵袭，血管生成和细胞死亡有关。接下来，为了鉴定PARVA的直接下游信号传导途径，使用转录因子靶模型进一步分析了371个显着改变PARVA的基因。十大PARVA改变的转录因子中有七个共享一个共同的上游介体ILK。最后，我们发现PARVA与SGK1和ILK形成复合物以增强ILK的磷酸化，从而导致Akt和GSK3β的磷酸化。值得注意的是，ILK的失活逆转了PARVA诱导的侵袭。两者合计，我们的发现暗示PARVA通过激活ILK充当致癌基因，并且该激活之后是Akt的激活和GSK3β的抑制。据我们所知，