Wilms' tumor 1 (WT1) promotes ovarian cancer progression by regulating E-cadherin and ERK1/2 signaling

Cell Cycle. 2020 Oct;19(20):2662-2675. doi: 10.1080/15384101.2020.1817666. Epub 2020 Sep 7.

Abstract

Wilms' tumor 1 (WT1) is reported to play an important role in tumor invasion and metastasis, two hallmarks of ovarian cancer (OC) that influence treatment efficacy and prognosis. However, the specific roles and underlying mechanisms of WT1 in OC have not been fully understood. Here, we investigated the potential function and signaling pathways of WT1 in OC cells. We showed that WT1 was significantly upregulated in human OC tissues and closely associated with OC type, grade and FIGO stage. In cultured cells and xenograft mouse models, WT1 depletion significantly inhibited cell migration and invasion, reversed epithelial-mesenchymal transition (EMT), and prevented metastasis of OC cells. We further demonstrated that WT1 inhibited E-cadherin expression via targeting E-cadherin gene promoter by chromatin immunoprecipitation and luciferase reporter assay. Moreover, ERK1/2 activation was suppressed upon WT1 silencing. Inhibiting ERK1/2 phosphorylation increased E-cadherin expression and suppressed WT1-induced OC cell migration and invasion. Taken together, our study reveals WT1 exerts a tumor-promoting role in OC, enhancing EMT through negative modulation of E-cadherin expression via ERK1/2 signaling. WT1 may represent a novel therapeutic target that may improve the prognosis of OC.

Keywords: WT1; EMT; ERK1/2 signaling; Ovarian cancer; migration and invasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics*
  • Cadherins / genetics*
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Disease Progression
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System / genetics*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Promoter Regions, Genetic / genetics
  • Signal Transduction / genetics*
  • WT1 Proteins / genetics*

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • WT1 Proteins
  • WT1 protein, human

Grants and funding

This work was supported by the National Key Research and Development Program of China under Grant number [2018YFC1004203 and 2018YFC1003703]; Major Project of Nanjing Medical University under Grant number [XJ2018001603]; Key Project of Science and Technology Innovation of Nanjing Medical University under Grant number [2017NJMUCX007]; and Science Plan Program of Nantong under Grant number [MS12019004 and MS12018007].