doi: 10.3967/bes2018.090
The Bidirectional Effects of Arsenic on miRNA-21: A Systematic Review and Meta-analysis
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Abstract:
Objective Arsenic is a metalloid environmental carcinogen involved in the occurrence and development of many cancers. miRNA-21 plays a crucial role in arsenic-induced carcinogenesis. We aimed to elucidate the mechanism by which miRNA-21 influences arsenic-induced cancer. Methods We used meta-analysis of published studies to determine how arsenic induces cancerous cells through miRNA-21. Results Low-dose arsenic exposure (≤ 5 μmol/L) can increase miRNA-21 and phosphorylated signal transducter and activator of transcription 3 (pSTAT3) expression, and decrease programmed cell death protein 4 (PDCD4) and protein sprouty homolog 1 (Spry1) expression. High-dose arsenic exposure (> 5 μmol/L), can increase miRNA-21 expression, and decrease Spry1 and E-cadherin expression. Short-term arsenic exposure (≤ 24 h) can increase miRNA-21 and pSTAT3 expression, and decrease PDCD4 expression. Moreover, long-term arsenic exposure (> 24 h) can increase the miRNA-21, STAT3, and pSTAT3 expression, and decrease PDCD4 expression. We found that activation of miRNA-21 and pSTAT3 were most pronounced following long-term arsenic exposure at low doses, and the effects on PDCD4 expression were most pronounced following short-term arsenic exposure at low doses. miRNA-21 inhibitors increased the expression of tumor suppressor genes PDCD4, PTEN, and Spry1 and miRNA-21-mimics suppressed the expression of these tumor suppressor genes. Conclusion Arsenic can cause cancer by activating miRNA-21 and inhibiting the expression of PDCD4, PTEN, and Spry1. -
Figure 1. Flow chart of the methodology used to identify studies for inclusion in the meta-analysis.
Figure 2. Risk of bias graph. This study included 17 articles with a low risk rate of more than 75 percent.
Figure 3. Effect of arsenic on malignant cell proliferation. SMD, standardized mean difference; E-cadherin, a type of cell adhesion molecule; N-cadherin, a type of cell adhesion molecule; Vimentin, a type Ⅲ intermediate filament (IF) protein. Arsenic can inhibit the expression of E-cadherin and N-cadherin, promote the expression of Vimentin, and cause malignant proliferation of cells.
Figure 4. The Effect of ARSENIC on STAT3. Forest plot shows the effect of arsenic treatment on STAT3 in treated and control groups. SMD, standardized mean difference; Ⅳ, independent variable; 95% CI, 95% confidence interval; SD, standard deviation. Arsenic cannot change the expression of STAT3.
Figure 5. The Effect of ARSENIC on pSTAT3. Forest plot shows the effect of arsenic treatment on pSTAT3 in treated and control groups. SMD, standardized mean difference; Ⅳ, independent variable; 95% CI, 95% confidence interval; SD, standard deviation. Arsenic can promote the expression of pSTAT3.
Figure 6. The Effect of ARSENIC on miRNA-21. Forest plot shows the effect of arsenic treatment on miRNA-21 expression in treatment and control groups. SMD, standardized mean difference; Ⅳ, independent variable; 95% CI, 95% confidence interval; SD, standard deviation. Arsenic can promote the expression of miRNA-21.
Figure 7. The effect of arsenic on PDCD4, PTEN, and Spry1. PDCD4, programmed cell death protein 4; PTEN, phosphatase and tensin homolog; Spry1, protein sprouty homolog 1. SMD, standardized mean difference. Arsenic can inhibit the expression of PDCD4, PTEN and Spry1 in cells.
Figure 8. The effects of arsenic on PDCD4, PTEN, and Spry1. SMD, standardized mean difference; PDCD4, programmed cell death protein 4; PTEN, phosphatase and tensin homolog; Spry1, protein sprouty homolog 1; anti-miRNA-21, miRNA-21 inhibitor; miRNA-21 mimic, miRNA-21 agonist. Compared with arsenic group, anti-miRNA-21 could promote the expression of PDCD4, PTEN, and Spry1; miRNA-21-mimic could inhibit the expression of PDCD4, PTEN, and Spry1.
Figure 9. Dose-response relationship between arsenic and miRNA-21. Analysis of the relationship between arsenic and miRNA-21 by spline model in random effects model. The dotted line indicates the 95% CI of the spline model. The solid line indicates the mean difference of the spline model.
Figure 10. Subgroup analysis of arsenic exposure dose. SMD, standardized mean difference. miRNA-21, An endogenous non-coding RNA; STAT3, signal transducer and activator of transcription 3; pSTAT3, phosphorylated signal transduction and activator of transcription 3; PDCD4, programmed cell death protein 4; PTEN, phosphatase and tensin homolog; Spry1, protein sprouty homolog 1; E-cadherin, a type of cell adhesion molecule. Arsenic can promote the expression of miRNA-21 under low or high dose exposure. The inhibitory effect of low dose of arsenic on PDCD4 and Spry1 was more obvious. The inhibitory effect of high dose arsenic on pSTAT3 and E-cadherin is more obvious.
Figure 11. Subgroup analysis of arsenic exposure time. SMD, standardized mean difference. miRNA-21, An endogenous non-coding RNA; STAT3, signal transducer and activator of transcription 3; pSTAT3, phosphorylated signal transduction and activator of transcription 3; PDCD4, programmed cell death protein 4. Prolonged arsenic exposure could promote the expression of miRNA-21 and STAT3 and inhibit the expression of pSTAT3 and PDCD4.
Figure 12. The funnel plot of miRNA-21. Blue-dotted line shows overall estimated standard mean difference. Evidence for publication bias was not found (P = 0.53). SMD, standard mean difference; SE, standard error; miRNA-21, an endogenous non-coding RNA.
Figure 13. Sensitivity analysis for miRNA-21. Stable results were observed for all included studies, indicating that no individual study influenced the combined results. CI, confidence interval; miRNA-21, an endogenous non-coding RNA.
Table 1. Characteristics of the Studies Included in the Meta-analysis
Authors Year Language n Arsenic Type Arsenic Dose (μmol/L) Exposure Duration (h) Outcome Indicators Country Lu Xiaolin et al.[12] 2015 English 3 NaAsO2 ≤ 5 ≤ 24 1, 2, 3, 7, 9 China Ling Min et al.[13] 2012 English 3 NaAsO2 ≤ 5 ≤ 24 1, 4, 5, 6 China Pratheeshkumar et al.[6] 2016 English 3 As2O3 > 5 > 24 1, 2, 3, 4, 7 America Gu Jingyi et al.[9] 2011 English 3 As2O3 ≤ 5 ≤ 24 1 China Luo Fei et al.[8] 2013 English 3 NaAsO2 ≤ 5 ≤ 24 1, 2, 3, 7, 8, 9 China Liu Xinlu et al.[4] 2016 English 3 NaAsO2 > 5 ≤ 24 1, 4, 5, 6 China Banerjee Nilanjana et al.[15] 2017 English 45 As2O3 ≤ 5 > 24 4, 5 India Xu Yuan et al.[16] 2015 English 3 NaAsO2 ≤ 5 ≤ 24 2, 3, 5 China Luo Fei et al.[17] 2015 English 3 NaAsO2 ≤ 5 ≤ 24 1, 4, 7, 8, 9 China Li Yumin et al.[18] 2010 English 3 As2O3 ≤ 5 ≤ 24 4 China Zhao Yue et al.[19] 2013 English 3 NaAsO2 ≤ 5 > 24 1 China Zhao Xin et al.[20] 2015 English 6 As2O3 ≤ 5 ≤ 24 1, 6 China Lu Shen et al.[21] 2013 English 3 NaAsO2 ≤ 5 ≤ 24 1, 6 China Cárdenas-González M et al.[10] 2016 English 27 As2O3 ≤ 5 > 24 1 Mexico Sun Jiaying et al.[7] 2014 English 3 As2O3 > 5 ≤ 24 1, 2, 3 China Chen Bailing et al.[22] 2013 English 3 As2O3 > 5 ≤ 24 1, 2, 3 China Li Yumin et al.[23] 2010 Chinese 3 As2O3 ≤ 5 ≤ 24 4 China He Qian et al.[34] 2013 English 3 As2O3 ≤ 5 > 24 1, 4, 5 China Lu Lu et al.[35] 2018 English 3 As2O3 > 5 > 24 1, 5 China Liu Haiwei et al.[36] 2018 English 3 As2O3 > 5 ≤ 24 1, 5 China Note. n, number within the experimental group; miRNA-21, an endogenous non-coding RNA; STAT3, signal transducer and activator of transcription 3; pSTAT3, phosphorylated signal transduction and activator of transcription 3; PDCD4, programmed cell death protein 4; PTEN, phosphatase and tensin homolog; Spry1, protein sprouty homolog 1; E-cadherin, a type of cell adhesion molecule; N-cadherin, a type of cell adhesion molecule; Vimentin, a type Ⅲ intermediate filament protein. 1, miRNA-21; 2, STAT3; 3, pSTAT3; 4, PDCD4; 5, PTEN; 6, Spry1; 7, E-cadherin; 8, N-cadherin; 9, Vimentin. 
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Table 2. Comprehensive Dose-response Data from Five Articles on miRNA-21 at Different Doses of Arsenic
ID Author Year Dose [Mean ± SD) μmol/L] 0 2 5 10 15 20 1 Pratheeshkumar et al.[6] 2016 10.30 ± 0.01 13.56 ± 0.14 15.43 ± 0.04 13.54 ± 0.02 - - 2 Liu Xinlu et al.[4] 2016 10.02 ± 0.12 15.32 ± 0.14 11.73 ± 0.11 10.42 ± 0.13 9.23 ± 0.16 - 3 Gu J (K562) et al.[9] 2011 10.34 ± 1.23 13.56 ± 2.43 16.34 ± 2.43 15.87 ± 2.13 14.32 ± 1.90 13.42 ± 1.63 4 Gu J (K562) et al.[9] 2011 11.00 ± 7.13 11.50 ± 7.01 15.80 ± 6.93 13.31 ± 7.32 11.67 ± 7.32 - 5 Sun J et al.[7] 2014 10.60 ± 5.32 11.30 ± 5.14 12.43 ± 5.43 11.43 ± 6.92 - - Note. Comprehensive dose-response data from five articles on miRNA-21 at different doses of arsenic. Dose, the dose of arsenic. Mean, the average expression of miRNA-21 under arsenic. SD, standard deviation of miRNA-21 expression under arsenic.
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