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PMID: 15937546 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Distinct mechanisms of TGF-beta1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis.

The Journal of clinical investigation ·Vol. 115 ·No. 7 ·2005-07-00 ·Pages 1714-23

Han G, Lu SL, Li AG, He W, Corless CL, Kulesz-Martin M, Wang XJ

Abstract

In the present study, we demonstrated that human skin cancers frequently overexpress TGF-beta1 but exhibit decreased expression of the TGF-beta type II receptor (TGF-(beta)RII). To understand how this combination affects cancer prognosis, we generated a transgenic mouse model that allowed inducible expression of TGF-beta(1) in keratinocytes expressing a dominant negative TGF-(beta)RII (Delta(beta)RII) in the epidermis. Without Delta(beta)RII expression, TGF-beta1 transgene induction in late-stage, chemically induced papillomas failed to inhibit tumor growth but increased metastasis and epithelial-to-mesenchymal transition (EMT), i.e., formation of spindle cell carcinomas. Interestingly, Delta(beta)RII expression abrogated TGF-beta1-mediated EMT and was accompanied by restoration of membrane-associated E-cadherin/catenin complex in TGF-beta1/Delta(beta)RII compound tumors. Furthermore, expression of molecules thought to mediate TGF-beta1-induced EMT was attenuated in TGF-beta1/Delta(beta)RII-transgenic tumors. However, TGF-beta1/Delta(beta)RII-transgenic tumors progressed to metastasis without losing expression of the membrane-associated E-cadherin/catenin complex and at a rate higher than those observed in nontransgenic, TGF-beta1-transgenic, or Delta(beta)RII-transgenic mice. Abrogation of Smad activation by Delta(beta)RII correlated with the blockade of EMT. However, Delta(beta)RII did not alter TGF-beta1-mediated expression of RhoA/Rac and MAPK, which contributed to increased metastasis. Our study provides evidence that TGF-beta1 induces EMT and invasion via distinct mechanisms. TGF-beta1-mediated EMT requires functional TGF-(beta)RII, whereas TGF-beta1-mediated tumor invasion cooperates with reduced TGF-(beta)RII signaling in tumor epithelia.

MeSH Terms
Animals Carcinoma in Situ/etiology,genetics,pathology Carcinoma, Squamous Cell/etiology,genetics,pathology,secondary DNA-Binding Proteins/genetics Epithelium/pathology Gene Expression Humans Mesoderm/pathology Mice Mice, Inbred ICR Mice, Transgenic Models, Biological Protein Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta/genetics Signal Transduction Skin Neoplasms/etiology,genetics,pathology Smad2 Protein Trans-Activators/genetics Transforming Growth Factor beta/genetics,physiology Transforming Growth Factor beta1
Chemicals
DNA-Binding Proteins Receptors, Transforming Growth Factor beta SMAD2 protein, human Smad2 Protein Smad2 protein, mouse TGFB1 protein, human Tgfb1 protein, mouse Trans-Activators Transforming Growth Factor beta Transforming Growth Factor beta1 Protein Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type II
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Han Gangwen
Department of Otolaryngology, Oregon Health & Science University, Portland, OR, USA.
Lu Shi-Long
Li Allen G
He Wei
Corless Christopher L
Kulesz-Martin Molly
Wang Xiao-Jing
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI24399
Published
2005-07-00
Epub
2005-00-02
Pages
1714-23
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1142114
Subset
IM
Grants
NCI NIH HHS · R01 CA079998 · United States
NCI NIH HHS · R01 CA087849 · United States
NCI NIH HHS · CA79998 · United States
NCI NIH HHS · CA87849 · United States
External Links
PubMed source DOI: 10.1172/JCI24399 PMC Full Text View journal details
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