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Kleinschmidt EG , Miller NLG , Ozmadenci D , Tancioni I , Osterman CD , Barrie AM , Taylor KN , Ye A , Jiang S , Connolly DC , Stupack DG , Schlaepfer DD
Rgnef promotes ovarian tumor progression and confers protection from oxidative stress
Oncogene. 2019 Sep;38(36) :6323-6337
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Abstract
Ovarian cancer is the fifth-leading cause of cancer death among women. The dissemination of ovarian tumors and growth as spheroids accompanies late-stage disease. In cell culture, ovarian tumor cell spheroids can exhibit elevated resistance to environmental stressors, such as reactive oxygen species. Homeostatic balance of the antioxidant response is a protective mechanism that prevents anoikis, a form of programmed cell death. Signaling pathways activated by integrin receptors suppress anoikis. Rgnef (ARHGEF28/p190RhoGEF) is a guanine nucleotide exchange factor that is activated downstream of integrins. We find that Rgnef protein levels are elevated in late-stage serous ovarian cancer, high Rgnef mRNA levels are associated with decreased progression-free and overall survival, and genomic ARHGEF28 loss is associated with increased patient survival. Using transgenic and transplantable Rgnef knockout mouse models, we find that Rgnef is essential for supporting three-dimensional ovarian spheroid formation in vitro and tumor growth in mice. Using RNA-sequencing and bioinformatic analyses, we identify a conserved Rgnef-supported anti-oxidant gene signature including Gpx4, Nqo1, and Gsta4; common targets of the NF-kB transcription factor. Antioxidant treatment enhanced growth of Rgnef-knockout spheroids and Rgnef re-expression facilitated NF-kappaB-dependent tumorsphere survival. These studies reveal a new role for Rgnef in ovarian cancer to facilitate NF-kappaB-mediated gene expression protecting cells from oxidative stress.
Notes
1476-5594 Kleinschmidt, Elizabeth G Miller, Nichol L G Ozmadenci, Duygu Tancioni, Isabelle Osterman, Carlos Diaz Barrie, Allison M Taylor, Kristin N Ye, Aaron Jiang, Shulin Connolly, Denise C Stupack, Dwayne G Schlaepfer, David D T32-CA121938/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) Journal Article England Oncogene. 2019 Sep;38(36):6323-6337. doi: 10.1038/s41388-019-0881-8. Epub 2019 Jul 15.