Yuan Hong, Kajiyama Hiroaki, Ito Satoko, Chen Dan, Shibata Kiyosumi, Hamaguchi Michinari, Kikkawa Fumitaka, Senga Takeshi
Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Oncotarget. 2015 May 30;6(15):13359-70. doi: 10.18632/oncotarget.3673.
Homeoproteins, a family of transcription factors that have conserved homeobox domains, play critical roles in embryonic development in a wide range of species. Accumulating studies have revealed that homeoproteins are aberrantly expressed in multiple tumors and function as either tumor promoters or suppressors. In this study, we show that two homeoproteins, HOXB13 and ALX4, are associated with epithelial to mesenchymal transition (EMT) and invasion of ovarian cancer cells. HOXB13 and ALX4 formed a complex in cells, and exogenous expression of either protein promoted EMT and invasion. Conversely, depletion of either protein suppressed invasion and induced reversion of EMT. SLUG is a C2H2-type zinc-finger transcription factor that promotes EMT in various cell lines. Knockdown of HOXB13 or ALX4 suppressed SLUG expression, and exogenous expression of either protein promoted SLUG expression. Finally, we showed that SLUG expression was essential for the HOXB13- or ALX4-mediated EMT and invasion. Our results show that HOXB13/SLUG and ALX4/SLUG axes are novel pathways that promote EMT and invasion of ovarian cancer cells.
同源异型蛋白是一类具有保守同源异型框结构域的转录因子，在多种物种的胚胎发育中发挥关键作用。越来越多的研究表明，同源异型蛋白在多种肿瘤中异常表达，并且具有肿瘤促进因子或抑制因子的功能。在本研究中，我们发现两种同源异型蛋白HOXB13和ALX4与卵巢癌细胞的上皮-间质转化（EMT）及侵袭相关。HOXB13和ALX4在细胞中形成复合物，任一蛋白的外源性表达均可促进EMT和侵袭。相反，任一蛋白的缺失均会抑制侵袭并诱导EMT逆转。SLUG是一种C2H2型锌指转录因子，可促进多种细胞系中的EMT。敲低HOXB13或ALX4可抑制SLUG表达，而任一蛋白的外源性表达均可促进SLUG表达。最后，我们表明SLUG表达对于HOXB13或ALX4介导的EMT和侵袭至关重要。我们的结果表明，HOXB13/SLUG和ALX4/SLUG轴是促进卵巢癌细胞EMT和侵袭的新途径。
