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Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin
Transforming growth factor β (TGF-β) has been shown to promote tumor invasion and metastasis by activating the matrix metalloproteinases (MMPs); however, signaling mechanisms remain controversial and therapies targeting MMPs are still suboptimal. In the present study, we found that combined therapy...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873580/ https://www.ncbi.nlm.nih.gov/pubmed/33614911 http://dx.doi.org/10.1016/j.omto.2021.01.006 |
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author | Lian, Guang-Yu Wang, Qing-Ming Mak, Thomas Shiu-Kwong Huang, Xiao-Ru Yu, Xue-Qing Lan, Hui-Yao |
author_facet | Lian, Guang-Yu Wang, Qing-Ming Mak, Thomas Shiu-Kwong Huang, Xiao-Ru Yu, Xue-Qing Lan, Hui-Yao |
author_sort | Lian, Guang-Yu |
collection | PubMed |
description | Transforming growth factor β (TGF-β) has been shown to promote tumor invasion and metastasis by activating the matrix metalloproteinases (MMPs); however, signaling mechanisms remain controversial and therapies targeting MMPs are still suboptimal. In the present study, we found that combined therapy with Asiatic acid (AA), a Smad7 agonist, and Naringenin (NG), a Smad3 inhibitor, effectively retrieved the balance between Smad3 and Smad7 signaling in the TGF-β-rich tumor microenvironment and thus significantly suppressed tumor invasion and metastasis in mouse models of melanoma and lung carcinoma. Mechanistically, we unraveled that Smad3 acted as a transcriptional activator of MMP2 and as a transcriptional suppressor of tissue inhibitors of metalloproteinase-2 (TIMP2) via binding to 5′ UTR of MMP2 and 3′ UTR of TIMP2, respectively. Treatment with NG inhibited Smad3-mediated MMP2 transcription while increasing TIMP, whereas treatment with AA enhanced Smad7 to suppress TGF-β/Smad3 signaling, as well as the activation of MMP2 by targeting the nuclear factor-κB (NF-κB)-membrane-type-1 MMP (MT1-MMP) axis. Therefore, the combination of AA and NG additively suppressed invasion and metastasis of melanoma and lung carcinoma by targeting TGF-β/Smad-dependent MMP2 transcription, post-translational activation, and function. |
format | Online Article Text |
id | pubmed-7873580 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-78735802021-02-19 Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin Lian, Guang-Yu Wang, Qing-Ming Mak, Thomas Shiu-Kwong Huang, Xiao-Ru Yu, Xue-Qing Lan, Hui-Yao Mol Ther Oncolytics Original Article Transforming growth factor β (TGF-β) has been shown to promote tumor invasion and metastasis by activating the matrix metalloproteinases (MMPs); however, signaling mechanisms remain controversial and therapies targeting MMPs are still suboptimal. In the present study, we found that combined therapy with Asiatic acid (AA), a Smad7 agonist, and Naringenin (NG), a Smad3 inhibitor, effectively retrieved the balance between Smad3 and Smad7 signaling in the TGF-β-rich tumor microenvironment and thus significantly suppressed tumor invasion and metastasis in mouse models of melanoma and lung carcinoma. Mechanistically, we unraveled that Smad3 acted as a transcriptional activator of MMP2 and as a transcriptional suppressor of tissue inhibitors of metalloproteinase-2 (TIMP2) via binding to 5′ UTR of MMP2 and 3′ UTR of TIMP2, respectively. Treatment with NG inhibited Smad3-mediated MMP2 transcription while increasing TIMP, whereas treatment with AA enhanced Smad7 to suppress TGF-β/Smad3 signaling, as well as the activation of MMP2 by targeting the nuclear factor-κB (NF-κB)-membrane-type-1 MMP (MT1-MMP) axis. Therefore, the combination of AA and NG additively suppressed invasion and metastasis of melanoma and lung carcinoma by targeting TGF-β/Smad-dependent MMP2 transcription, post-translational activation, and function. American Society of Gene & Cell Therapy 2021-01-20 /pmc/articles/PMC7873580/ /pubmed/33614911 http://dx.doi.org/10.1016/j.omto.2021.01.006 Text en © 2021 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Original Article Lian, Guang-Yu Wang, Qing-Ming Mak, Thomas Shiu-Kwong Huang, Xiao-Ru Yu, Xue-Qing Lan, Hui-Yao Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin |
title | Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin |
title_full | Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin |
title_fullStr | Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin |
title_full_unstemmed | Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin |
title_short | Inhibition of tumor invasion and metastasis by targeting TGF-β-Smad-MMP2 pathway with Asiatic acid and Naringenin |
title_sort | inhibition of tumor invasion and metastasis by targeting tgf-β-smad-mmp2 pathway with asiatic acid and naringenin |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873580/ https://www.ncbi.nlm.nih.gov/pubmed/33614911 http://dx.doi.org/10.1016/j.omto.2021.01.006 |
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