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

Journal of Advanced Research

Kam Man Hui¹  Shobith Rangappa²  Manoj Garg³  Sulaiman Ali Alharbi⁴  Arunachalam Chinnathambi⁴  Tahani Awad Alahmadi⁵  Gautam Sethi⁶  Jong Hyun Lee⁷  Young Yun Jung⁷  Chakrabhavi Dhananjaya Mohan⁸  Salundi Basappa⁹  Amudha Deivasigamani^1,10  Kwang Seok Ahn^1,10  Zhi-Xiu Lin^1,11  Kanchugarakoppal S. Rangappa^1,12 

[1] Corresponding authors at: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore ( Gautam Sethi), Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore (Kam Man Hui), and Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea (Kwang Seok Ahn).;Adichunchanagiri Institute for Molecular Medicine, BG Nagara 571448, Nagamangala Taluk, India;Amity Institute of Molecular Medicine and Stem cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh 201313, India;Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia;Department of Pediatrics, College of Medicine and King Khalid University Hospital, King Saud University Medical City, Riyadh 11461, Saudi Arabia;Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore;Department of Science in Korean Medicine, College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea;Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, Mysore 570006, India;Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India;Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore;Faculty of Medicine, The Chinese University of Hong Kong, Rm 101, 1/F Li Wai Chun Building, CUHK, Shatin, N.T., Hong Kong;Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore 570006, India;

关键词: EMT;    Brusatol;    HCC;    Orthotopic mouse model;    Metastasis;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown