Hhex(human hematopoietically expressed homeobox), also known as PRH, is originally considered as a transcription factor to regulate gene expression due to its homebox domain. Increasing studies show that Hhex plays a significant role in development, including anterior–posterior axis formation, vascular development and HSCs self-renewal etc. Hhex is linked to many diseases such as cancers, leukemia, and type-2 diabetes. Although Hhex is reported to inhibit cell migration and invasion of breast and prostate epithelial cells by upregulating Endoglin expression, the effect and molecular mechanism for lung cancer cell motility regulation remains elusive. Human non-small cell lung cancer cells and HEK293FT cells were used to investigate the molecular mechanism of Hhex regulating lung cancer cell migration by using Western blot, immunoprecipitation, wound-healing scratch assay, laser confocal. Our data indicated that Hhex could inhibit cell migration and cell protrusion formation in lung cancer cells. In addition, Hhex inhibited CFL1 phosphorylation to keep its F-actin-severing activity. RHOGDIA was involved in Hhex-induced CFL1 phosphorylation regulation. Hhex enhanced RHOGDIA interaction with RHOA/CDC42, thus maintaining RHOA/CDC42 at an inactive form. Collectively, these data indicate that Hhex inhibited the activation of RHOA/CDC42 by enhancing interaction of RHOGDIA with RHOA/CDC42, and then RHOA/ CDC42-p-CFL1 signaling pathway was blocked. Consequently, the formation of Filopodium and Lamellipodium on the cell surface was suppressed, and thus the ability of lung cancer cells to migrate was decreased accordingly. Our findings show Hhex plays an important role in regulating migration of lung cancer cells and may provide a potential target for lung cancer therapy.

中文翻译：

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Hhex通过调节人肺癌细胞的RHOA/CDC42-CFL1轴抑制细胞迁移

Hhex（人类造血表达的同源框），也称为PRH，由于其homebox结构域，最初被认为是调节基因表达的转录因子。越来越多的研究表明，Hhex 在发育过程中发挥着重要作用，包括前后轴形成、血管发育和 HSC 自我更新等。Hhex 与许多疾病有关，如癌症、白血病和 2 型糖尿病。尽管据报道 Hhex 通过上调 Endoglin 表达来抑制乳腺和前列腺上皮细胞的细胞迁移和侵袭，但肺癌细胞运动调节的作用和分子机制仍然难以捉摸。以人非小细胞肺癌细胞和HEK293FT细胞为研究对象，采用Western blot、免疫沉淀、伤口愈合划痕测定，激光共聚焦。我们的数据表明，Hhex 可以抑制肺癌细胞中的细胞迁移和细胞突起形成。此外，Hhex 抑制 CFL1 磷酸化以保持其 F-肌动蛋白切断活性。RHOGDIA 参与了 Hhex 诱导的 CFL1 磷酸化调节。Hhex 增强了 RHOGDIA 与 RHOA/CDC42 的相互作用，从而将 RHOA/CDC42 维持在非活性形式。总之，这些数据表明，Hhex 通过增强 RHOGDIA 与 RHOA/CDC42 的相互作用来抑制 RHOA/CDC42 的激活，然后阻断 RHOA/CDC42-p-CFL1 信号通路。因此，细胞表面的丝状亚基和片状亚基的形成受到抑制，从而使肺癌细胞的迁移能力相应降低。