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Modulation of MnSOD and FoxM1 Is Involved in Invasion and EMT Suppression by Isovitexin in Hepatocellular Carcinoma Cells

Authors Qiu Y, Cao X, Liu L, Cao X, Yuan Q, Li X, Cui Y, Xu C, Zou C, Ren K, Cao J

Received 8 January 2020

Accepted for publication 28 May 2020

Published 14 July 2020 Volume 2020:12 Pages 5759—5771

DOI https://doi.org/10.2147/CMAR.S245283

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Sanjeev Srivastava


Yebei Qiu,1,2,* Xiaocheng Cao,1,2,* Lihua Liu,3,4 Xiaozheng Cao,3,4 Qing Yuan,5 Xiang Li,5 Yinghong Cui,1,5 Chang Xu,1,2 Chang Zou,4,6 Kaiqun Ren,1,2 Jianguo Cao1,2

1The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal University, Changsha 410013, People’s Republic of China; 2The Key Laboratory of Study and Discover of Small Targeted Molecules of Hunan Province, Medical College, Hunan Normal University, Changsha 410013, People’s Republic of China; 3Pharmacy Department, The Second Clinical Medical School of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, People’s Republic of China; 4Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen People’s Hospital, Shenzhen 518020, People’s Republic of China; 5Department of Preclinical Medicine, Medical College, Hunan Normal University, Changsha, Hunan 410013, People’s Republic of China; 6Clinical Medical Research Center, The Second Clinical Medical School of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jianguo Cao; Kaiqun Ren
Kaiqun Ren the Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal University, Changsha 410013, People’s Republic of China
Tel +86-0731-88912434
Email caojianguo2005@126.com; kaiqunren@126.com

Background: Manganese superoxide dismutase (MnSOD) induces FoxM1 expression, subsequently contributing to migration in several cancer cells. Isovitexin (ISOV) was recently found to downregulate MnSOD and FoxM1, decreasing stemness in hepatocellular carcinoma (HCC) stem-like cells (HCSLCs). The current study aimed to determine whether inhibition of migration, invasion and EMT in HCSLCs by ISOV results from MnSOD/FoxM1 signaling blockade and subsequent Twist1, Slug, ZEB1 and MMP-2 downregulation.
Materials and Methods: We examined the migratory and invasive capabilities and EMT phenotype in HCC cells and their HCSLCs, respectively, by wound-healing assay, transwell invasion assay and Western blot after treatment with non-cytotoxic concentrations of ISOV, and explored the mechanism by which ISOV affects migration, invasion and EMT by MnSOD or FoxM1 knockdown and/or overexpression in HCSLCs or HCC cells.
Results: The results showed that ISOV not only downregulated MnSOD and FoxM1 but also suppressed the migratory and invasive capabilities and reversed the EMT phenotype in HCSLCs, which was reflected by elevated E-cadherin protein amounts, and reduced N-cadherin, Twist1, Slug, ZEB1 and MMP-2 protein levels. The suppressive effects of ISOV on the migratory and invasive capabilities and EMT phenotype could be potentiated by MnSOD or FoxM1 knockdown in HCSLCs, and attenuated by MnSOD or FoxM1 overexpression in HCC cells. Importantly, FoxM1 overexpression reversed MnSOD knockdown combined with ISOV suppression on the migratory and invasive capabilities and EMT phenotype in HCSLCs, while having little effects on MnSOD expression.
Conclusion: Collectively, the above findings demonstrated that ISOV suppresses migration, invasion and EMT in HCSLCs by blocking MnSOD/FoxM1 signaling subsequently inhibiting the expression of EMT-related transcription factors and MMP-2.

Keywords: hepatocellular carcinoma, cancer stem cell, isovitexin, epithelial-mesenchymal transition, MnSOD, FoxM1, Twist1, MMP-2

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