The Wilms’ tumor gene WT1 −17AA/−KTS splice variant increases tumorigenic activity through up-regulation of vascular endothelial growth factor in an in vivo ovarian cancer model

Keiko Yamanouchi, Tsuyoshi Ohta, Zhiyang Liu, Yusuke Oji, Haruo Sugiyama, Viji Shridhar, Sohei Matsumura, Toshifumi Takahashi, Kazuhiro Takahashi, Hirohisa Kurachi

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

TheWilms' tumor 1 gene WT1 encodes a zinc transcription factor involved in a variety of cancer-related processes. In this study, we sought to investigate the effects ofWT1 splice variants on tumorigenic activity and survival in an in vivo ovarian cancermodel. To this end, we established stable ovarian cancer cell lines transduced with lentiviral constructs containing each of the four WT1 splice variants (−17AA/−KTS, +17AA/−KTS, −17AA/+KTS, and +17AA/+KTS). Inmice inoculated intraperitoneally with SKOV3ip1 cells expressingWT1 −17AA/−KTS, disseminated tumor weights and production of asciteswere significantly increased compared with those inmice inoculatedwith cells expressing the control vector. The overall survival inmice inoulatedwithWT1−17AA/−KTS-expressing cells was significantly shorter than that in mice inoculated with control cells (P =.0115). Immunoblot analysis revealed that WT1 −17AA/−KTS significantly increased the expression of vascular endothelial growth factor (VEGF) compared with the control. Greater numbers of CD31-immunopositive vessels were observed in tumors from mice injected with cells expressing WT1 −17AA/−KTS than in tumors from control mice. Finally, WT1 −17AA/−KTS significantly increased tumor microvessel density compared with that in the control (P b.05). Treatment with anti-VEGF antibody (bevacizumab) inhibited tumor growth, dissemination, and ascites production in mice injected with cells expressingWT1−17AA/−KTS. The overexpression ofWT1 −17AA/−KTS induced a more aggressive phenotype in ovarian cancer cells through VEGF up-regulation in an in vivo ovarian cancer model. Our findings indicated thatWT1 −17AA/−KTS enhanced tumorigenic activity and could decreased patient survival through up-regulation of VEGF expression in ovarian cancers.

Original languageEnglish (US)
Pages (from-to)580-589
Number of pages10
JournalTranslational Oncology
Volume7
Issue number5
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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