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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Published on: April 26, 2017

Modification of HER2 pre-mRNA alternative splicing and its effects on breast cancer cells

Jing Wan1, Peter Sazani, Ryszard Kole

  • 1Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295, USA. jingwan@med.unc.edu

International Journal of Cancer
|November 28, 2008
PubMed

Insights

A novel splice switching oligonucleotide (SSO111) effectively targets the oncogene HER2 by inducing exon skipping. This approach downregulates HER2 and generates a soluble form, Delta15HER2, showing potential for new HER2-targeted cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • HER2 oncogene overexpression is common in various human cancers.
  • Targeting HER2 is a key strategy in anti-cancer molecular therapies.
  • Alternative splicing of HER2 pre-mRNA can produce variants with therapeutic potential.

Purpose of the Study:

  • To investigate the efficacy of a 2'-O-methoxyethyl (MOE) splice switching oligonucleotide (SSO111) in targeting HER2.
  • To analyze the effects of SSO111-induced HER2 pre-mRNA splicing on HER2 expression and cell behavior.
  • To characterize the functional properties of the novel Delta15HER2 splice variant.

Main Methods:

  • Utilized SSO111 to induce exon 15 skipping in HER2 pre-mRNA.
  • Treated HER2-overexpressing SK-BR-3 cells with SSO111.
  • Analyzed HER2 mRNA levels (full-length and Delta15HER2) and cell proliferation/apoptosis.
  • Investigated the effects of exogenous Delta15HER2 protein on HER2 signaling pathways.

Main Results:

  • SSO111 treatment significantly downregulated full-length HER2 mRNA and upregulated Delta15HER2 mRNA.
  • SSO111 inhibited proliferation and induced apoptosis in SK-BR-3 cells.
  • The Delta15HER2 mRNA encodes a soluble, secreted receptor form.
  • Exogenous Delta15HER2 protein reduced membrane-bound HER2 and HER3 transphosphorylation, mimicking autoinhibitory HER2 variants.

Conclusions:

  • SSO111 is a promising therapeutic agent for inducing HER2 downregulation via splice switching.
  • The Delta15HER2 splice variant exhibits tumor-suppressive properties.
  • Both SSO111 and Delta15HER2 represent potential candidates for novel HER2-targeted cancer therapeutics.

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