J Cancer 2019; 10(26):6716-6725. doi:10.7150/jca.35626

Research Paper

Metastasis-associated protein 2 regulates human hepatocellular carcinoma metastasis progression through modulating p38MAPK/MMP2 pathways

Wen-Hung Hsu1, Hui-Ling Chiou2, Chia-Liang Lin3, Shao-Hsuan Kao3, Hsiang-Lin Lee4,5, Chung-Jung Liu1,6✉*, Yi-Hsien Hsieh3,7,8✉*

1. Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
2. School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan
3. Institute of Biochemistry, Microbiology, and Immunology, Chung Shan Medical University, Taichung, Taiwan
4. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
5. Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
6. Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan
7. Department of Biochemistry, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
8. Clinical laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan
*These authors contributed equally to this work

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Citation:
Hsu WH, Chiou HL, Lin CL, Kao SH, Lee HL, Liu CJ, Hsieh YH. Metastasis-associated protein 2 regulates human hepatocellular carcinoma metastasis progression through modulating p38MAPK/MMP2 pathways. J Cancer 2019; 10(26):6716-6725. doi:10.7150/jca.35626. Available from http://www.jcancer.org/v10p6716.htm

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Abstract

Studies have shown the overexpression of metastasis-associated protein 2 (MTA2) to be associated with hepatocellular carcinoma (HCC) progression. However, the molecular mechanism of MTA2 expression in HCC is unclear. In our study, we found a higher level of MTA2 in HCC tissues than in normal tissues and a significant correlation between tumor grade and overall survival of HCC patients. We also found that MTA2 inhibition reduced the migration and invasion capabilities of HCC cells, independent of cell proliferation. Mechanistic studies have suggested that MTA2 protein and mRNA are more highly expressed in SK-Hep-1 and Huh-7 cells compared with other HCC cells. MTA2 silencing drastically reduced migration and invasion capability and also inhibited matrix metalloproteinase 2 (MMP2) at the transcriptional and translation levels in both cells. In addition, treatment with the MMP2 antibody markedly impaired MTA2-knockdown-mediated inhibition of migration and invasion in SK-Hep-1 cells. Furthermore, MTA2 knockdown reduced the phosphorylation of the p38MAPK protein, whereas the inhibition of p38MAPK (SB203580 or si-p38) confirmed that blocking the p38MAPK pathway mediated MTA2-knockdown-inhibited migration and invasion in SK-Hep-1 cells. We demonstrated the molecular mechanism by which MTA2 inhibits human HCC cell metastasis through the p38MAPK/MMP2 pathways, which might be helpful in determining the diagnostic value of this protein in patients with HCC

Keywords: Hepatocellular carcinoma cell, MTA2, Migration, Invasion, p38MAPK, MMP-2