Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression
Rhonda L. Brown, … , Jing Yang, Chonghui Cheng
Rhonda L. Brown, … , Jing Yang, Chonghui Cheng
Published February 14, 2011
Citation Information: J Clin Invest. 2011;121(3):1064-1074. https://doi.org/10.1172/JCI44540.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 7

CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression

  • Text
  • PDF
Abstract

Epithelial-mesenchymal transition (EMT) is a tightly regulated process that is critical for embryogenesis but is abnormally activated during cancer metastasis and recurrence. Here we show that a switch in CD44 alternative splicing is required for EMT. Using both in vitro and in vivo systems, we have demonstrated a shift in CD44 expression from variant isoforms (CD44v) to the standard isoform (CD44s) during EMT. This isoform switch to CD44s was essential for cells to undergo EMT and was required for the formation of breast tumors that display EMT characteristics in mice. Mechanistically, the splicing factor epithelial splicing regulatory protein 1 (ESRP1) controlled the CD44 isoform switch and was critical for regulating the EMT phenotype. Additionally, the CD44s isoform activated Akt signaling, providing a mechanistic link to a key pathway that drives EMT. Finally, CD44s expression was upregulated in high-grade human breast tumors and was correlated with the level of the mesenchymal marker N-cadherin in these tumors. Together, our data suggest that regulation of CD44 alternative splicing causally contributes to EMT and breast cancer progression.

Authors

Rhonda L. Brown, Lauren M. Reinke, Marin S. Damerow, Denise Perez, Lewis A. Chodosh, Jing Yang, Chonghui Cheng

×

Figure 4

The splicing factor ESRP1 regulates CD44 isoform switching during EMT.

Options: View larger image (or click on image) Download as PowerPoint
The splicing factor ESRP1 regulates CD44 isoform switching during EMT.
(...
(A) qRT-PCR analysis of ESRP1 levels in HMLE/Twist-ER cells during TAM-induced EMT. (B) Relative luciferase activity (left) and semiquantitative RT-PCR analysis (right) in 293 cells cotransfected with ESRP1 and a CD44v5 luciferase reporter construct, indicating that ESRP1 promotes inclusion of CD44 variable exons. (C) Left: qRT-PCR analysis showing knockdown efficiency of ESRP1 in HMLE cells using two different shRNAs. Right: Immunoblot analysis showing decreased expression of CD44v and increased expression of CD44s in HMLE cells in which ESRP1 has been silenced. (D) Immunoblot analysis of CD44 and EMT markers in control and ESRP1-overexpressing HMLE/Twist-ER cells before (untreated) and after 14 days of TAM treatment (left), demonstrating that ESRP1 overexpression inhibits both the CD44 isoform switch and EMT. Immunofluorescence imaging (right) shows that overexpression of ESRP1 results in maintenance of E-cadherin at cell junctions during TAM-induced EMT in HMLE/Twist-ER cells, as compared with control cells. (E) Immunoblot analysis of EMT markers in HMLE cells expressing ESRP1 shRNA alone or in combination with CD44 shRNA before (untreated) and after 14 days of TGF-β treatment. Silencing ESRP1 promotes EMT, and loss of CD44 in the ESRP1-silenced cells leads to preservation of expression of epithelial markers E-cadherin, γ-catenin, and occludin and impaired upregulation of mesenchymal markers N-cadherin and vimentin following TGF-β treatment.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Referenced in 2 patents
Highlighted by 1 platforms
369 readers on Mendeley
See more details