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Citations to this article

Distinct mechanisms of TGF-β1–mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis
Gangwen Han, … , Molly Kulesz-Martin, Xiao-Jing Wang
Gangwen Han, … , Molly Kulesz-Martin, Xiao-Jing Wang
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1714-1723. https://doi.org/10.1172/JCI24399.
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Research Article Oncology Article has an altmetric score of 6

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

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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 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.

Authors

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

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2007 2006 Total
Citations: 1 1 1 3 7 4 3 4 4 5 8 6 5 12 3 9 10 6 7 2 101
Citation information
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Citations to this article in year 2011 (3)

Title and authors Publication Year
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

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ISSN: 0021-9738 (print), 1558-8238 (online)

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