Oligonucleotide-directed STAT3 alternative splicing switch drives anti-tumorigenic outcomes in MCF10 human breast cancer cells

Vincent Tano, David A. Jans, Marie A. Bogoyevitch

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Abstract

Signal transducer and activator of transcription 3 (STAT3), a transcription factor responsive to the activation of cytokine receptors, is known for its oncogenic actions. Whilst STAT3α is the predominant spliceform in most tissues, alternative splicing of the STAT3 gene can generate a shorter STAT3β spliceform. Redirecting splicing to enhance STAT3β levels can result in tumor suppression in vivo, and so we evaluated the cellular basis underlying the anti-tumorigenic properties of STAT3β. To investigate the impact of increased STAT3β levels in cancer cells, we implemented a Morpholino-based antisense oligonucleotide strategy to modulate STAT3 spliceform expression in the MCF10CA1h cancer cells of the MCF10 series of human breast cancer cells. We employed nonsense-mediated decay (NMD)oligonucleotides and STAT3α-to-β expression switching (SWI)oligonucleotides to successfully induce STAT3 knockdown and redirect alternative splicing to increase STAT3β levels in MCF10CA1h cells, respectively. Importantly, assessment of the impacts of STAT3 splicing modulation on tumor cell biology showed that the SWI treatment significantly reduced MCF10CA1h cell growth, viability, and migration, whereas NMD treatment was without significant impact, although neither NMD nor SWI oligonucleotides significantly inhibited MCF10CA1h cell invasion through a semi-solid matrix. In conclusion, our data demonstrate that reduced breast cancer cell growth, viability and migration, but not invasion, follow the redirection of STAT3α-to-β expression switching to favour STAT3β expression.

Original languageEnglish
Pages (from-to)1076-1082
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume513
Issue number4
DOIs
Publication statusPublished - 11 Jun 2019

Keywords

  • Breast cancer
  • Invasion
  • Morpholino oligonucleotide
  • Proliferation
  • STAT3
  • Viability

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