Research Paper|Volume 16, Issue 17|pp 12239—12251

MTA2 knockdown suppresses human osteosarcoma metastasis by inhibiting uPA expression

Chun Tseng^1,^2,^3,⁴, Chien-Min Chen^5,^6,⁷, Yi-Hsien Hsieh⁸, Chia-Yu Lin^2,³, Jian-Wen Chen^2,³, Pang-Hsuan Hsiao^2,⁹, Yi-Chin Fong^2,^3,⁹, Pei-Han Wang⁸, Pei-Ni Chen⁸, Renn-Chia Lin^10,¹¹

¹Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
²Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan
³Spine Center, China Medical University Hospital, Taichung, Taiwan
⁴Department of Orthopedic Surgery, China Medical University Beigang Hospital, Yunlin, Taiwan
⁵Division of Neurosurgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
⁶Department of Leisure Industry Management, National Chin-Yi University of Technology, Taichung, Taiwan
⁷Department of Biomedical Sciences National Chung Cheng University, Chiayi, Taiwan
⁸Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
⁹Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan
¹⁰Department of Orthopedics, Chung Shan Medical University Hospital, Taichung, Taiwan
¹¹School of Medicine, Chung Shan Medical University, Taichung, Taiwan

* Equal contribution

Received: February 23, 2024Accepted: July 17, 2024Published: September 6, 2024

https://doi.org/10.18632/aging.206070

Copyright: © 2024 Tseng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The relationship between metastasis-associated protein 2 (MTA2) overexpression and tumor growth and metastasis has been extensively studied in a variety of tumor cells but not in human osteosarcoma cells. This study aims to elucidate the clinical significance, underlying molecular mechanisms, and biological functions of MTA2 in human osteosarcoma in vitro and in vivo. Our results show that MTA2 was elevated in osteosarcoma cell lines and osteosarcoma tissues and was associated with tumor stage and overall survival of osteosarcoma patients. Knockdown of MTA2 inhibited osteosarcoma cell migration and invasion by reducing the expression of urokinase-type plasminogen activator (uPA). Bioinformatic analysis demonstrated that high levels of uPA in human osteosarcoma tissues correlated positively with MTA2 expression. Furthermore, treatment with recombinant human uPA (Rh-uPA) caused significant restoration of OS cell migration and invasion in MTA2 knockdown osteosarcoma cells. We found that ERK1/2 depletion increased the expression of uPA, facilitating osteosarcoma cell migration and invasion. Finally, MTA2 depletion significantly reduced tumor metastasis and the formation of lung nodules in vivo. Overall, our study suggests that MTA2 knockdown suppresses osteosarcoma cell metastasis by decreasing uPA expression via ERK signaling. This finding provides new insight into potential treatment strategies against osteosarcoma metastasis by targeting MTA2.