Tseng C.-H.Murray K.D.Jou M.-F.Hsu S.-M.Cheng H.-J.PEI-HSIN HUANG2020-03-052020-03-0520111932-6203https://www.scopus.com/inward/record.uri?eid=2-s2.0-79955758096&doi=10.1371%2fjournal.pone.0019396&partnerID=40&md5=b81de87eb6d312047f5696ccf51429a7https://scholars.lib.ntu.edu.tw/handle/123456789/470834Cancer cells often employ developmental cues for advantageous growth and metastasis. Here, we report that an axon guidance molecule, Sema3E, is highly expressed in human high-grade ovarian endometrioid carcinoma, but not low-grade or other ovarian epithelial tumors, and facilitates tumor progression. Unlike its known angiogenic activity, Sema3E acted through Plexin-D1 receptors to augment cell migratory ability and concomitant epithelial-to-mesenchymal transition (EMT). Sema3E-induced EMT in ovarian endometrioid cancer cells was dependent on nuclear localization of Snail1 through activation of phosphatidylinositol-3-kinase and ERK/MAPK. RNAi-mediated knockdown of Sema3E, Plexin-D1 or Snail1 in Sema3E-expressing tumor cells resulted in compromised cell motility, concurrent reversion of EMT and diminished nuclear localization of Snail1. By contrast, forced retention of Snail1 within the nucleus of Sema3E-negative tumor cells induced EMT and enhanced cell motility. These results show that in addition to the angiogenic effects of Sema3E on tumor vascular endothelium, an EMT strategy could be exploited by Sema3E/Plexin-D1 signaling in tumor cells to promote cellular invasion/migration. ? 2011 Tseng et al.[SDGs]SDG3mitogen activated protein kinase; phosphatidylinositol 3 kinase; plexin; plexin D1 receptor; semaphorin; semaphorin 3E; transcription factor Snail; unclassified drug; isoprotein; nerve cell adhesion molecule; PLXND1 protein, human; SEMA3E protein, human; semaphorin; adult; animal tissue; article; cancer cell; cancer grading; cancer growth; cancer invasion; cell migration; cell motility; cell nucleus; clinical article; controlled study; endometrioid carcinoma; enzyme activation; epithelial mesenchymal transition; female; human; human cell; metastasis potential; nonhuman; nucleotide sequence; ovary cancer; protein determination; protein expression; protein function; protein localization; RNA interference; signal transduction; tumor vascularization; cell motion; epithelium; gene expression regulation; mesoderm; metabolism; metastasis; ovary tumor; physiology; tumor cell line; Carcinoma, Endometrioid; Cell Adhesion Molecules, Neuronal; Cell Line, Tumor; Cell Movement; Cell Nucleus; Epithelium; Female; Gene Expression Regulation, Neoplastic; Humans; Mesoderm; Neoplasm Invasiveness; Neoplasm Metastasis; Ovarian Neoplasms; Protein Isoforms; Semaphorins; Signal Transductionjournal article10.1371/journal.pone.0019396215593682-s2.0-79955758096