Molecular mechanism of metastasis-associated protein 3 involvement in glioma drug resistance through reactive oxygen_West China Medical Journal

Authors：

 ZHANG Yingjie ¹ , WU Zaihui ¹ , LI Xiaolong ² , LI Lin ³

1. Neurosurgery Department, Tangshan Hongci Hospital, Tangshan, Hebei 063000, P. R. China;
2. Neurosurgery Department, Shijiazhuang Great Wall Integrated Traditional Chinese and Western Medicine Hospital, Shijiazhuang, Hebei 050000, P. R. China;
3. Neurosurgery Department, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, P. R. China;

Corresponding author：

ZHANG Yingjie, Email: stowner120@163.com

Keywords：

Metastasis-associated protein 3; reactive oxygen; glioma; drug resistance

DOI：

10.7507/1002-0179.202305202

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the molecular mechanism by which metastasis-associated protein 3 (MTA3) participates in glioma resistance through reactive oxygen species. Methods Protein expression in glioma stem cells (GSCs) and non-GSCs was detected using Western blotting. GSCs included U87 and SHG44 cells, while non-GSCs included U87s and SU-2 cells. After overexpressing MTA3, U87 and SHG44 cells were divided into Lv-scr and Lv-MTA3 groups. The self-renewal capacity of glioma cells was assessed through a neurosphere formation assay. Cell survival fractions were examined following exposure to 0, 2, 4, 6, 8, and 10 Gy X-ray irradiation under normoxic or hypoxic conditions. Apoptosis and reactive oxygen species expression were analyzed using flow cytometry. Immunofluorescence staining was performed to detect the stem cell markers CD133 and nestin, as well as the differentiation markers glial fibrillary acidic protein (GFAP, for astrocytes) and neuronal class Ⅲ β-tubulin. Results In GSCs, MTA3 expression was lower in the U87s and SU-2 groups. After MTA3 overexpression, Lv-MTA3 expression was higher in U87s and SU-2 compared to the Lv-scr group. Under normoxic or hypoxic conditions, U87 and SU-2 showed greater radioresistance compared to glioma cell lines U87 and SHG44. Compared to non-GSCs, basal reactive oxygen species formation was reduced in GSCs, while reactive oxygen species generation was increased in non-GSCs. Following exposure to different doses of X-rays under normoxic or hypoxic conditions, GSCs with MTA3 overexpression exhibited greater radiosensitivity than those with stable integration. Additionally, MTA3 overexpression slightly increased the oxygen enhancement ratio (OER) in GSCs. MTA3 overexpression reduced the immunoreactivity of CD133 and nestin in both stem cell lines, and increased immunofluorescence staining of GFAP and neuronal class Ⅲ β-tubulin, with statistically significant differences (P<0.05). Conclusions MTA3 is downregulated in GSCs. Overexpression of MTA3 reduces the radioresistance and stemness of GSCs both in vitro and in vivo. MTA3 plays a crucial role in regulating the radiosensitivity and stemness of GSCs through reactive oxygen species.

Citation： ZHANG Yingjie, WU Zaihui, LI Xiaolong, LI Lin. Molecular mechanism of metastasis-associated protein 3 involvement in glioma drug resistance through reactive oxygen. West China Medical Journal, 2024, 39(5): 732-738. doi: 10.7507/1002-0179.202305202 Copy

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6.	Du L, Wang L, Gan J, et al. MTA3 represses cancer stemness by targeting the SOX₂OT/SOX₂ axis. iScience, 2019, 22: 353-368.
7.	Horii M, Moretto-Zita M, Nelson KK, et al. MTA3 regulates differentiation of human cytotrophoblast stem cells. Placenta, 2015, 36(9): 974-980.
8.	Fujita N, Jaye DL, Kajita M, et al. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell, 2003, 113(2): 207-219.
9.	Jiao T, Li Y, Gao T, et al. MTA3 regulates malignant progression of colorectal cancer through Wnt signaling pathway. Tumour Biol, 2017, 39(3): 1010428317695027.
10.	Lau P, Zhang G, Zhao S, et al. Sphingosine kinase 1 promotes tumor immune evasion by regulating the MTA3-PD-L1 axis. Cell Mol Immunol, 2022, 19(10): 1153-1167.
11.	Liu J, Wang X, Chen AT, et al. ZNF117 regulates glioblastoma stem cell differentiation towards oligodendroglial lineage. Nat Commun, 2022, 13(1): 2196.
12.	Li Q, Li Z, Lin Y, et al. High glucose promotes hepatic fibrosis via miR-32/MTA3-mediated epithelial-to-mesenchymal transition. Mol Med Rep, 2019, 19(4): 3190-3200.
13.	李海英, 王庆苓, 张琳, 等. MTA3 在肺癌细胞中调控细胞凋亡机制的研究. 中国肺癌杂志, 2015, 18(10): 610-615.
14.	Wang Y, Qi H, Liu Y, et al. The double-edged roles of ROS in cancer prevention and therapy. Theranostics, 2021, 11(10): 4839-4857.
15.	Fukai T, Ushio-Fukai M. Cross-talk between NADPH oxidase and mitochondria: role in ROS signaling and angiogenesis. Cells, 2020, 9(8): 1849.
16.	Najafi M, Mortezaee K, Majidpoor J. Cancer stem cell (CSC) resistance drivers. Life Sci, 2019, 234: 116781.

1. Zhao N, Zhang J, Zhao Q, et al. Mechanisms of long non-coding RNAs in biological characteristics and aerobic glycolysis of glioma. Int J Mol Sci, 2021, 22(20): 11197.
2. Boyd NH, Tran AN, Bernstock JD, et al. Glioma stem cells and their roles within the hypoxic tumor microenvironment. Theranostics, 2021, 11(2): 665-683.
3. Huang H, Yu X, Han X, et al. Piwil1 regulates glioma stem cell maintenance and glioblastoma progression. Cell Rep, 2021, 34(1): 108522.
4. Kapoor-Narula U, Lenka N. Elucidating the anti-tumorigenic efficacy of oltipraz, a dithiolethione, in glioblastoma. Cells, 2022, 11(19): 3057.
5. Choi HS, Kim SL, Kim JH, et al. Plant volatile, phenylacetaldehyde targets breast cancer stem cell by induction of ros and regulation of stat3 signal. Antioxidants (Basel), 2020, 9(11): 1119.
6. Du L, Wang L, Gan J, et al. MTA3 represses cancer stemness by targeting the SOX₂OT/SOX₂ axis. iScience, 2019, 22: 353-368.
7. Horii M, Moretto-Zita M, Nelson KK, et al. MTA3 regulates differentiation of human cytotrophoblast stem cells. Placenta, 2015, 36(9): 974-980.
8. Fujita N, Jaye DL, Kajita M, et al. MTA3, a Mi-2/NuRD complex subunit, regulates an invasive growth pathway in breast cancer. Cell, 2003, 113(2): 207-219.
9. Jiao T, Li Y, Gao T, et al. MTA3 regulates malignant progression of colorectal cancer through Wnt signaling pathway. Tumour Biol, 2017, 39(3): 1010428317695027.
10. Lau P, Zhang G, Zhao S, et al. Sphingosine kinase 1 promotes tumor immune evasion by regulating the MTA3-PD-L1 axis. Cell Mol Immunol, 2022, 19(10): 1153-1167.
11. Liu J, Wang X, Chen AT, et al. ZNF117 regulates glioblastoma stem cell differentiation towards oligodendroglial lineage. Nat Commun, 2022, 13(1): 2196.
12. Li Q, Li Z, Lin Y, et al. High glucose promotes hepatic fibrosis via miR-32/MTA3-mediated epithelial-to-mesenchymal transition. Mol Med Rep, 2019, 19(4): 3190-3200.
13. 李海英, 王庆苓, 张琳, 等. MTA3 在肺癌细胞中调控细胞凋亡机制的研究. 中国肺癌杂志, 2015, 18(10): 610-615.
14. Wang Y, Qi H, Liu Y, et al. The double-edged roles of ROS in cancer prevention and therapy. Theranostics, 2021, 11(10): 4839-4857.
15. Fukai T, Ushio-Fukai M. Cross-talk between NADPH oxidase and mitochondria: role in ROS signaling and angiogenesis. Cells, 2020, 9(8): 1849.
16. Najafi M, Mortezaee K, Majidpoor J. Cancer stem cell (CSC) resistance drivers. Life Sci, 2019, 234: 116781.

West China Medical Journal

Molecular mechanism of metastasis-associated protein 3 involvement in glioma drug resistance through reactive oxygen

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