Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Feb 8;16(4):3231-3240.
doi: 10.18632/aging.205531. Epub 2024 Feb 8.

Sodium tanshinone IIA sulfonate inhibits tumor growth via miR-138 upregulation in intermittent hypoxia-induced xenograft mice

Xiao-Bin Zhang  1   2 , Qi-Feng Gan  1   3 , Xiu-Zhen He  1 , Ya-Ting Yuan  1 , Ling-Wang  1 , Mao-Hong Huang  1 , Ping-Yang Hong  1
Affiliations

Sodium tanshinone IIA sulfonate inhibits tumor growth via miR-138 upregulation in intermittent hypoxia-induced xenograft mice

Xiao-Bin Zhang et al. Aging (Albany NY). .

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.

Keywords: intermittent hypoxia; miR-138; sodium tanshinone IIA sulfonate; tumor.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Effect of IH and TSA on miR-138 expression in vitro. (A) RNA sequence results demonstrate the fold_change in miR-138. (B) RT-qPCR verified the miR-138 expression in different groups.
Figure 2
Figure 2
Effect of TSA on tumor growth in IH-exposed xenograft mice. (A) Change in body weight of mice at the indicated week. (B) Change in the tumor volume on the indicated day. (C) Comparison of tumor weight between different groups. (D) Tumor images in different groups.
Figure 3
Figure 3
Effect of TSA on miR-138 levels in IH-exposed xenograft mice. RT-qPCR results demonstrate the miR-138 expression of tumor tissue between different groups.
Figure 4
Figure 4
Effects of TSA on HIF-1α and VEGF levels in IH-exposed xenograft mice. (A) IHC of HIF-1α expression. (B) Western blotting results of HIF-1α. (C) Serum VEGF levels between groups with ELISA detection. (D) Western blotting results of VEGF.
Figure 5
Figure 5
Effects of TSA on tumor migration, invasion, MVD, and apoptosis in IH-exposed xenograft mice. (A) Western blotting of tumor migration and invasion biomarkers, N-cadherin, catenin, MMP9, and MMP3. (B) MVD levels between different groups. (C) Western blotting of apoptosis biomarkers, BAX, and Caspase-3. (D) TUNEL assay images and results between different groups.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Kendzerska T, Povitz M, Leung RS, Boulos MI, McIsaac DI, Murray BJ, Bryson GL, Talarico R, Hilton JF, Malhotra A, Gershon AS. Obstructive Sleep Apnea and Incident Cancer: A Large Retrospective Multicenter Clinical Cohort Study. Cancer Epidemiol Biomarkers Prev. 2021; 30:295–304. 10.1158/1055-9965.EPI-20-0975 - DOI - PMC - PubMed
    1. Kendzerska T, Gershon AS, Povitz M, Boulos MI, Murray BJ, McIsaac DI, Bryson GL, Talarico R, Hilton J, Malhotra A, Leung RS. Polysomnographic Markers of Obstructive Sleep Apnea Severity and Cancer-related Mortality: A Large Retrospective Multicenter Clinical Cohort Study. Ann Am Thorac Soc. 2022; 19:807–18. 10.1513/AnnalsATS.202106-738OC - DOI - PMC - PubMed
    1. Campos-Rodriguez F, Martinez-Garcia MA, Martinez M, Duran-Cantolla J, Peña Mde L, Masdeu MJ, Gonzalez M, Campo Fd, Gallego I, Marin JM, Barbe F, Montserrat JM, Farre R, and Spanish Sleep Network. Association between obstructive sleep apnea and cancer incidence in a large multicenter Spanish cohort. Am J Respir Crit Care Med. 2013; 187:99–105. 10.1164/rccm.201209-1671OC - DOI - PubMed
    1. Tan BKJ, Teo YH, Tan NKW, Yap DWT, Sundar R, Lee CH, See A, Toh ST. Association of obstructive sleep apnea and nocturnal hypoxemia with all-cancer incidence and mortality: a systematic review and meta-analysis. J Clin Sleep Med. 2022; 18:1427–40. 10.5664/jcsm.9772 - DOI - PMC - PubMed
    1. Huang MH, Zhang XB, Wang HL, Li LX, Zeng YM, Wang M, Zeng HQ. Intermittent hypoxia enhances the tumor programmed death ligand 1 expression in a mouse model of sleep apnea. Ann Transl Med. 2019; 7:97. 10.21037/atm.2019.01.44 - DOI - PMC - PubMed

Publication types