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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Smad4 Loss in Mouse Keratinocytes Leads to Increased Susceptibility to UV Carcinogenesis with Reduced Ercc1-Mediated DNA Repair
D Mitra, P Fernandez, L Bian, N Song, F Li, G Han, XJ Wang |
Journal of Investigative Dermatology | 2013 |
The epigenetics of epithelial-mesenchymal plasticity in cancer
WL Tam, RA Weinberg |
Nature Medicine | 2013 |
Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer
A Montagner, MB Delgado, C Tallichet-Blanc, JS Chan, MK Sng, H Mottaz, G Degueurce, Y Lippi, C Moret, M Baruchet, M Antsiferova, S Werner, D Hohl, TA Saati, PJ Farmer, NS Tan, L Michalik, W Wahli |
EMBO Molecular Medicine | 2013 |
PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway
NG Her, SI Jeong, K Cho, TK Ha, J Han, KP Ko, SK Park, JH Lee, MG Lee, BK Ryu, SG Chi |
Cell cycle (Georgetown, Tex.) | 2013 |
The role of microRNA-200 in progression of human colorectal and breast cancer
L Bojmar, E Karlsson, S Ellegård, H Olsson, B Björnsson, O Hallböök, M Larsson, O Stål, P Sandström |
PloS one | 2013 |