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 ΔβRII 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/ΔβRII–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.
Gangwen Han, Shi-Long Lu, Allen G. Li, Wei He, Christopher L. Corless, Molly Kulesz-Martin, Xiao-Jing Wang
Title and authors | Publication | Year |
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Outgrowth of Drug-Resistant Carcinomas Expressing Markers of Tumor Aggression after Long-term TβRI/II Kinase Inhibition with LY2109761
EC Connolly, EF Saunier, D Quigley, MT Luu, AD Sapio, B Hann, JM Yingling, RJ Akhurst |
Cancer research | 2011 |
Genome-wide screening of indicator genes for assessing the potential carcinogenic risk of Nanjing city drinking water
R Zhang, S Cheng, A Li, J Sun, Y Zhang, X Zhang |
Ecotoxicology | 2011 |
The complexities of TGF-β action during mammary and squamous cell carcinogenesis.
Connolly EC, Akhurst RJ |
Current pharmaceutical biotechnology | 2011 |