Research Paper Volume 16, Issue 4 pp 3231—3240
Sodium tanshinone IIA sulfonate inhibits tumor growth via miR-138 upregulation in intermittent hypoxia-induced xenograft mice
- 1 Department of Pulmonary and Critical Care Medicine, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People's Republic of China
- 2 The School of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China
- 3 School of Medicine, Xiamen University, Xiamen, Fujian, People’s Republic of China
Received: September 22, 2023 Accepted: January 8, 2024 Published: February 8, 2024
https://doi.org/10.18632/aging.205531How to Cite
Copyright: © 2024 Zhang 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
Purpose: We studied the functions of sodium tanshinone IIA sulfonate (TSA) in inducing tumor growth in obstructive sleep apnea (OSA)-mimicking intermittent hypoxia (IH) xenograft mice and the underlying potential molecular mechanism.
Methods: RNA sequencing was conducted to screen the differentially expressed microRNAs in cell lines exposed to IH with or without TSA treatment. As part of the 5-week in vivo study, we treated xenograft mice with 8-h IH once daily. TSA and miR-138 inhibitors or mimics were administrated appropriately. In addition, we performed real-time quantitative polymerase chain reaction (RT-PCR), Western blotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), microvessel density (MVD), and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays.
Results: RNA sequencing and RT-PCR results demonstrated that TSA increased the levels of miR-138 under IH conditions in vitro. TSA reduced the IH-stimulated high levels of hypoxia-induced factor-1α and vascular endothelial growth factor. Furthermore, IH contributed to high tumor migration, invasion, MVD, and low apoptosis. TSA attenuated IH-mediated tumor proliferation, migration, invasion, MVD, and increased apoptosis, whereas miR-138 inhibitor interrupted the effect of TSA on treating IH-induced tumor behaviors.
Conclusions: OSA mimicking IH facilitates tumor growth and reduces miR-138 levels. TSA inhibits IH-induced tumor growth by upregulating the expression of miR-138.
Abbreviations
OSA: Obstructive sleep apnea; IH: Intermittent hypoxia; TSA: Sodium tanshinone IIA sulfonate; LLC: Lewis lung cancer; HIF-1α: Hypoxia-induced factor-1α; BAX: B-cell lymphoma 2-associated protein X; VEGF: Vascular endothelial growth factor; MMP9: Matrix metalloproteinase 9; MMP3: Matrix metalloproteinase 3; CTL: Control; DE: Differential expression; DEGseq: Differential expression gene sequence; RT-qPCR: Real-time quantitative polymerase chain reaction; ELISA: Enzyme-linked immunosorbent assay; HE: Hematoxylin-eosin; IHC: Immunohistochemistry; IOD: Integrated optical density; MVD: Microvessel density; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick-end labeling.