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Int J Med Sci 2020; 17(4):457-470. doi:10.7150/ijms.38832 This issue Cite

Research Paper

Oxidative Stress Down-Regulates MiR-20b-5p, MiR-106a-5p and E2F1 Expression to Suppress the G1/S Transition of the Cell Cycle in Multipotent Stromal Cells

Lihui Tai^1,2,*, Chiu-Jung Huang^3✉, Kong Bung Choo^1,4✉, Soon Keng Cheong^1,5, Tunku Kamarul⁶

1. Centre for Stem Cell Research, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
2. Postgraduate Program, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia;
3. Department of Animal Science & Graduate Institute of Biotechnology, Chinese Culture University, Taipei, Taiwan;
4. Department of Preclinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
5. Dean's Office, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia;
6. Tissue Engineering Group, National Orthopedic Centre of Excellence for Research and Learning & Department of Orthopedic Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
* Present address: MAKNA Cancer Research Institute, Kuala Lumpur, Malaysia

✉ Corresponding authors: Kong Bung Choo, PhD, Senior Professor, Faculty of Medicine and Health Sciences & Centre for Stem Cell Research, Universiti Tunku Abdual Rahman, Sungai Long Campus, Kajang, Selangor, Malaysia. Email: chookbedu.my or Chiu-Jung Huang, PhD, Professor, Department of Animal Science & Graduate Institute of Biotechnology, Chinese Culture University, Taipei, Taiwan. Email: hqr2pccu.edu.tw More

Abstract

Oxidative stress has been linked to senescence and tumorigenesis via modulation of the cell cycle. Using a hydrogen peroxide (H₂O₂)-induced oxidative stress-induced premature senescence (OSIPS) model previously reported by our group, this study aimed to investigate the effects of oxidative stress on microRNA (miRNA) expression in relation to the G1-to-S-phase (G1/S) transition of the cell cycle and cell proliferation. On global miRNA analysis of the OSIPS cells, twelve significantly up- or down-regulated miRNAs were identified, the target genes of which are frequently associated with cancers. Four down-regulated miR-17 family miRNAs are predicted to target key pro- and anti-proliferative proteins of the p21/cyclin D-dependent kinase (CDK)/E2F1 pathway to modulate G1/S transition. Two miR-17 miRNAs, miR-20-5p and miR-106-5p, were confirmed to be rapidly and stably down-regulated under oxidative stress. While H₂O₂ treatment hampered G1/S transition and suppressed DNA synthesis, miR-20b-5p/miR-106a-5p over-expression rescued cells from growth arrest in promoting G1/S transition and DNA synthesis. Direct miR-20b-5p/miR-106a-5p regulation of p21, CCND1 and E2F1 was demonstrated by an inverse expression relationship in miRNA mimic-transfected cells. However, under oxidative stress, E2F1 expression was down-regulated, consistent with hampered G1/S transition and suppressed DNA synthesis and cell proliferation. To explain the observed E2F1 down-regulation under oxidative stress, a scheme is proposed which includes miR-20b-5p/miR-106a-5p-dependent regulation, miRNA-E2F1 autoregulatory feedback and E2F1 response to repair oxidative stress-induced DNA damages. The oxidative stress-modulated expression of miR-17 miRNAs and E2F1 may be used to develop strategies to retard or reverse MSC senescence in culture, or senescence in general.

Keywords: oxidative stress, miR-20b-5p & miR-106a-5p, miR-17 family, p21/CDK/E2F1 pathway, E2F1, G1/S transition of cell cycle

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