title: Distinct mechanisms of TGF-beta1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis.
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.
authors.affiliation: Department of Otolaryngology, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Gangwen
authors.initials: G
authors.lastname: Han
authors.forename: Shi-Long
authors.initials: SL
authors.lastname: Lu
authors.forename: Allen G
authors.initials: AG
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.forename: Molly
authors.initials: M
authors.lastname: Kulesz-Martin
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
mesh_terms: D000818:Animals; D002278:Carcinoma in Situ / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000556:secondary; D004268:DNA-Binding Proteins / Q000235:genetics; D004848:Epithelium / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D051899:Smad2 Protein; D015534:Trans-Activators / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1
chemical_list: D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II