期刊
MOLECULAR THERAPY-ONCOLYTICS
卷 20, 期 -, 页码 277-289出版社
CELL PRESS
DOI: 10.1016/j.omto.2021.01.006
关键词
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资金
- Guangdong-Hong Kong-Macao-Joint Labs Program from Guangdong Science and Technology [2019B121205005]
- Innovation and Technology Fund of Hong Kong [ITS/138/17]
- Research Grants Council of Hong Kong [GRF 14117418, 14104019]
The combined therapy with Asiatic acid and Naringenin effectively suppressed tumor invasion and metastasis by targeting TGF-beta/Smad-dependent MMP2 transcription. This approach retrieved the balance between Smad3 and Smad7 signaling in the tumor microenvironment.
Transforming growth factor beta (TGF-beta) 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-beta-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-beta/Smad3 signaling, as well as the activation of MMP2 by targeting the nuclear factor-kappa B (NF-kappa B)-membrane-type-1 MMP (MT1MMP) axis. Therefore, the combination of AA and NG additively suppressed invasion and metastasis of melanoma and lung carcinoma by targeting TGF-beta/Smad-dependent MMP2 transcription, post-translational activation, and function.
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