Research Paper Volume 12, Issue 8 pp 6644—6666
LncRNA Sox2OT-V7 promotes doxorubicin-induced autophagy and chemoresistance in osteosarcoma via tumor-suppressive miR-142/miR-22
- 1 Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
- 2 Department of Orthopedics, Xiangya Changde Hospital, Changde, Hunan 415000, China
- 3 Department of Pediatric Orthopedics, Hunan Provincial Peoples’ Hospital, Changsha, Hunan 410006, China
Received: September 26, 2019 Accepted: March 9, 2020 Published: April 16, 2020https://doi.org/10.18632/aging.103004
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Copyright © 2020 Zhu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Doxorubicin (Dox) is one of the most commonly used chemotherapeutic drugs for osteosarcoma (OS) treatment. In the present study, we attempted to investigate the mechanism by which Sox2OT-V7 dysregulation affects Dox chemoresistance to provide a novel experimental basis for developing neoadjuvant therapy. Sox2OT-V7 expression is upregulated in OS tissues, particularly in chemoresistant OS tissues, and in OS cell lines compared to controls. Dox treatment induces autophagy and Sox2OT-V7 expression in U2OS cells, and Dox-induced autophagy is partially attenuated by Sox2OT-V7 silencing. Knocking down Sox2OT-V7 or blocking autophagy in Dox-resistant U2OS/Dox cells resensitizes the cells to Dox treatment in vitro. Moreover, Sox2OT-V7 directly targets miR-142/miR-22 to inhibit their expression, and the effect of Sox2OT-V7 silencing on U2OS cell autophagy and U2OS/Dox cell sensitivity to Dox can be reversed by miR-142/miR-22 inhibition. Sox2OT-V7 silencing enhances the suppressive effects of Dox on U2OS/Dox cell-derived tumor growth in vivo, while miR-22 inhibition or miR-142 inhibition reverses the effects of Sox2OT-V7 silencing on Dox-induced suppression on tumor growth. Finally, miR-142 directly targets ULK1, ATG4A, and ATG5, while miR-22 directly targets ULK1 to inhibit the expression of the target gene; The Sox2OT-V7/miR-142/miR-22 axis modulates autophagy in OS cells by regulating ULK1, ATG4A, and ATG5.