Brusatol suppresses STAT3-driven metastasis by downregulating epithelial-mesenchymal transition in hepatocellular carcinoma

Lee, Jong Hyun and Mohan, Chakrabhavi Dhananjaya and Deivasigamani, Amudha and Jung, Young Yun and Rangappa, Shobith and Basappa, Salundi and Chinnathambi, Arunachalam and Alahmadi, Tahani Awad and Alharbi, Sulaiman Ali and Garg, Manoj and Lin, Zhi-Xiu and Rangappa, Kanchugarakoppal S. and Sethi, Gautam and Hui, Kam Man and Ahn, Kwang Seok (2020) Brusatol suppresses STAT3-driven metastasis by downregulating epithelial-mesenchymal transition in hepatocellular carcinoma. Journal of Advanced Research, 26. pp. 83-94. ISSN 2090-1224

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Introduction: Epithelial-mesenchymal transition (EMT) is a process of transdifferentiation where epithelial cells attain mesenchymal phenotype to gain invasive properties and thus, can contribute to metastasis of tumor cells. Objectives: The antimetastatic and antitumor efficacy of brusatol (BT) was investigated in a hepatocellular carcinoma (HCC) model. Methods: We evaluated the action of BT on EMT process using various biological assays in HCC cell lines and its effect on tumorigenesis in an orthotopic mouse model. Results: We found that BT treatment restored the expression of Occludin, E-cadherin (epithelial markers) while suppressing the levels of different mesenchymal markers in HCC cells and tumor tissues. Moreover, we observed a decline in the expression of transcription factors (Snail, Twist). Since the expression of these two factors can be regulated by STAT3 signaling, we deciphered the influence of BT on modulation of this pathway. BT suppressed the phosphorylation of STAT3Y705 and STAT3 depletion using siRNA resulted in the restoration of epithelial markers. Importantly, BT (1mg/kg) reduced the tumor burden in orthotopic mouse model with a concurrent decline in lung metastasis. Conclusions: Overall, our results demonstrate that BT interferes with STAT3 induced metastasis by altering the expression of EMT-related proteins in HCC model. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of Cairo University.

Item Type: Article
Uncontrolled Keywords: EMT; Brusatol; HCC; Orthotopic mouse model; Metastasis
Subjects: B Life Science > Molecular Biology
Divisions: Department of > Molecular Biology
Depositing User: Mr Umendra uom
Date Deposited: 29 Mar 2021 06:09
Last Modified: 29 Mar 2021 06:09

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