Distinct mechanisms of TGF-β1-mediated epithelial-to- mesenchymal transition and metastasis during skin carcinogenesis

Gangwen Han, Shi Long Lu, Allen G. Li, Wei He, Christopher L. Corless, Molly Kulesz-Martin, Xiao Jing Wang

Research output: Contribution to journalArticle

187 Scopus citations

Abstract

In the present study, we demonstrated that human skin cancers frequently overexpress TGF-β1 but exhibit decreased expression of the TGF-β type II receptor (TGF-βRII). To understand how this combination affects cancer prognosis, we generated a transgenic mouse model that allowed inducible expression of TGF-β1 in keratinocytes expressing a dominant negative TGF-βRII (ΔβRII) in the epidermis. Without AβRII expression, TGF-β1 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, ΔβRII expression abrogated TGF-β1-mediated EMT and was accompanied by restoration of membrane-associated E-cadherin/catenin complex in TGF-β1/ ΔβRII compound tumors. Furthermore, expression of molecules thought to mediate TGF-β1-induced EMT was attenuated in TGF-β1/AβRII-transgenic tumors. However, TGF-β1/ΔβRII-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-β1-transgenic, or ΔβRII-transgenic mice. Abrogation of Smad activation by ΔβRII correlated with the blockade of EMT. However, ΔβRII did not alter TGF-β1- mediated expression of RhoA/Rac and MAPK, which contributed to increased metastasis. Our study provides evidence that TGF-β1 induces EMT and invasion via distinct mechanisms. TGF-β1-mediated EMT requires functional TGF-βRII, whereas TGF-β1-mediated tumor invasion cooperates with reduced TGF-βRII signaling in tumor epithelia.

Original languageEnglish (US)
Pages (from-to)1714-1723
Number of pages10
JournalJournal of Clinical Investigation
Volume115
Issue number7
DOIs
StatePublished - Jul 2005

ASJC Scopus subject areas

  • Medicine(all)

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