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Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression.

Publication ,  Journal Article
Gordon, KJ; Dong, M; Chislock, EM; Fields, TA; Blobe, GC
Published in: Carcinogenesis
February 2008

Epithelial to mesenchymal transitions (EMTs) contribute to increases in cellular motility and invasiveness during embryonic development and tumorigenesis. The transforming growth factor beta (TGF-beta) signaling pathway is a key regulator of EMT. The TGF-beta superfamily coreceptor, the type III TGF-beta receptor (TbetaRIII or betaglycan), is required for EMT during embryonic heart development and palate fusion. Here, we establish that in a pancreatic cancer model of EMT, TbetaRIII expression is specifically lost during EMT at the mRNA and protein levels, whereas levels of the TGF-beta type I and type II receptors are maintained at the mRNA level. Loss of TbetaRIII expression at the protein level precedes the loss of E-cadherin and cytoskeletal reorganization during early stages of EMT. However, maintaining TbetaRIII expression does not block these aspects of EMT, but instead suppresses the increased motility and invasiveness associated with EMT. Reciprocally, shRNA-mediated knockdown of endogenous TbetaRIII increases cellular motility without affecting Snail or E-cadherin levels. The ability of TbetaRIII to suppress motility and invasiveness does not depend on its cytoplasmic domain or its coreceptor function. Instead, this suppression of invasion is partially mediated by ectodomain shedding of TbetaRIII, generating soluble TbetaRIII (sTbetaRIII). In human pancreatic cancer specimens, TbetaRIII expression decreases at both the mRNA and protein levels, with the degree of loss correlating with worsening tumor grade. Taken together, these studies support a role for loss of TbetaRIII expression during the EMT of pancreatic cancer progression, with a specific role for sTbetaRIII in suppressing EMT-associated increases in motility and invasion.

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Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

February 2008

Volume

29

Issue

2

Start / End Page

252 / 262

Location

England

Related Subject Headings

  • Receptors, Transforming Growth Factor beta
  • Proteoglycans
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Invasiveness
  • Models, Biological
  • Mesoderm
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Gene Expression Regulation
 

Citation

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Gordon, K. J., Dong, M., Chislock, E. M., Fields, T. A., & Blobe, G. C. (2008). Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression. Carcinogenesis, 29(2), 252–262. https://doi.org/10.1093/carcin/bgm249
Gordon, Kelly J., Mei Dong, Elizabeth M. Chislock, Timothy A. Fields, and Gerard C. Blobe. “Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression.Carcinogenesis 29, no. 2 (February 2008): 252–62. https://doi.org/10.1093/carcin/bgm249.
Journal cover image

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

February 2008

Volume

29

Issue

2

Start / End Page

252 / 262

Location

England

Related Subject Headings

  • Receptors, Transforming Growth Factor beta
  • Proteoglycans
  • Pancreatic Neoplasms
  • Oncology & Carcinogenesis
  • Neoplasm Invasiveness
  • Models, Biological
  • Mesoderm
  • Humans
  • Gene Expression Regulation, Neoplastic
  • Gene Expression Regulation