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Determination of WWOX Function in Modulating Cellular Pathways Activated by AP-2α and AP-2γ Transcription Factors in

Damian Kołat1, Żaneta Kałuzińska1, Andrzej K Bednarek1

  • 1Department of Molecular Carcinogenesis, Medical University of Lodz, 90-752 Lodz, Poland.

Cells
|May 14, 2022
PubMed

Insights

This study reveals WWOX and AP-2α signaling pathways are more similar than AP-2γ in bladder cancer. AP-2γ shows relevance for targeted therapy, with potential applications for differently regulated genes in bladder cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • High-throughput sequencing advanced cancer research but often overlooked tumor heterogeneity.
  • Understanding WWOX/AP-2α/AP-2γ roles in bladder cancer is crucial, as they influence carcinogenesis differently.
  • This study addresses tumor heterogeneity's impact on WWOX, AP-2α, and AP-2γ in bladder cancer.

Purpose of the Study:

  • To investigate signaling pathways regulated by WWOX-dependent AP-2 targets in bladder cancer cell lines.
  • To identify and functionally annotate key genes involved in these pathways.
  • To elucidate the distinct roles of WWOX, AP-2α, and AP-2γ in bladder cancer progression and their therapeutic relevance.

Main Methods:

  • Utilized high-throughput sequencing (CAGE-seq) on bladder cancer cell lines (RT-112, HT-1376, CAL-29) with lentiviral transduction.
  • Performed differential gene expression analysis, functional annotation, and network visualization.
  • Validated key gene expressions at the protein level using Western blot and analyzed pathway data.

Main Results:

  • Identified genes implicated in MAPK, Wnt, Ras, PI3K-Akt, and Rap1 signaling pathways.
  • Confirmed differential roles: WWOX as an EMT inhibitor, AP-2γ as an EMT enhancer, and AP-2α as a MET inducer.
  • Validated FGFR3, STAT6, EFNA1, GSK3B, PIK3CB, and SOS1 at the protein level; PCA explained phenotypic differences by gene expression.

Conclusions:

  • Signaling pathways regulated by WWOX and AP-2α share more similarities than those regulated by AP-2γ in bladder cancer.
  • The distinct roles in epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) highlight AP-2γ's relevance in targeted therapy.
  • Differentially regulated genes present potential therapeutic applications for bladder cancer treatment.
Keywords:
AP-2αAP-2γTFAP2ATFAP2CWWOXbioinformaticsbladdercancerfunctional genomicstarget genes

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