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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
07:49

Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling

Published on: August 3, 2018

MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell

William Kong1, Hua Yang, Lili He

  • 1Departments of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., SRB3, Tampa, FL 33612, USA.

Molecular and Cellular Biology
|September 17, 2008
PubMed

Insights

Transforming growth factor beta (TGF-beta) signaling promotes cancer metastasis. This study reveals microRNA-155 (miR-155) is upregulated by TGF-beta, driving cell migration and invasion by targeting RhoA, suggesting miR-155 as a therapeutic target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Transforming growth factor beta (TGF-beta) signaling is crucial for advanced malignancy progression.
  • The role of microRNAs (miRNAs) in TGF-beta-induced metastasis remains incompletely understood.
  • Protein-encoding genes are known contributors, but miRNA involvement requires further investigation.

Purpose of the Study:

  • To investigate the role of microRNAs (miRNAs) in TGF-beta-induced epithelial-mesenchymal transition (EMT), cell migration, and invasion.
  • To identify specific miRNAs deregulated by TGF-beta signaling in mammary epithelial cells.
  • To elucidate the molecular mechanism by which TGF-beta influences metastasis via miRNA regulation.

Main Methods:

  • Utilized a 515-miRNA oligonucleotide-based microarray to screen for deregulated miRNAs in TGF-beta-treated NMuMG cells.
  • Performed Smad4 knockdown experiments to confirm Smad4-dependent miRNA regulation.
  • Conducted miRNA knockdown and ectopic expression studies, along with RhoA manipulation, to assess functional impacts on cell phenotypes.
  • Analyzed clinical breast cancer tissues for miR-155 expression levels.

Main Results:

  • Identified 28 significantly deregulated miRNAs in TGF-beta-treated NMuMG cells, with miR-155 being the most upregulated.
  • Demonstrated that TGF-beta induces miR-155 expression and promoter activity via Smad4.
  • Showed that miR-155 knockdown inhibits TGF-beta-induced EMT, tight junction dissolution, cell migration, and invasion.
  • Confirmed that miR-155 targets RhoA, and its overexpression reduces RhoA levels and disrupts tight junctions, phenocopying TGF-beta effects.
  • Found elevated miR-155 levels in invasive human breast cancer tissues.

Conclusions:

  • miR-155 is a key mediator of TGF-beta-induced epithelial-mesenchymal transition (EMT), cell migration, and invasion.
  • The mechanism involves miR-155 targeting of RhoA, leading to disrupted tight junctions and enhanced metastatic potential.
  • miR-155 represents a potential therapeutic target for intervening in breast cancer metastasis.

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