We aimed to systematically evaluate the regulatory effect of arsenic on wnt/β-catenin signaling pathway and to provide theoretical basis for revealing the mechanism of the relationship between arsenic and cell proliferation. The meta-analysis was carried out using Revman5.2 and Stata13.0 to describe the differences between groups with standard mean difference. We found in normal cells that the levels of wnt3a, β-catenin, glycogen synthase kinase-3β phosphorylated at serine 9 (p-GSK-3β(Ser9)), cyclinD1, proto-oncogene c-myc, and vascular endothelial growth factor (VEGF) in the arsenic intervention group were higher than those in the control group, and the level of glycogen synthase kinase-3β (GSK-3β) was lower than that in the control group (P < 0.05, respectively). Subgroup analysis showed that for a long time period (>24 h), the level of β-catenin in the arsenic intervention group was higher than that in the control group, and the level of GSK-3β of the same long-time period (>24 h) with low-dose (≤5 μM) intervention was lower than those in the control group (P < 0.05, respectively). In cancer cells, the levels of β-catenin, cyclinD1, c-myc, and VEGF in the arsenic intervention group were lower than those in the control group, while the level of GSK-3β in the arsenic intervention group was higher than that in the control group (P < 0.05, respectively). Subgroup analysis showed that the levels of β-catenin, cyclinD1, and c-myc in the high-dose (>5 μM) arsenic intervention group were lower than those in the control group, and the levels of β-catenin and cyclinD1 in the high-dose (>5 μM) arsenic intervention group were lower than those in the low-dose (≤5 μM) arsenic intervention group (P < 0.05, respectively). In addition, the regulation of arsenic on β-catenin was dose-dependent in the range of arsenic concentration from 0 to 7.5 μM. This study revealed that arsenic could upregulate wnt/β-catenin signaling pathway in normal cells and downregulate it in cancer cells, and its effect was affected by time and dose.

Objectives Malignant cell proliferation is one of the important mechanisms of arsenic poisoning. A large number of studies have shown that STAT3 plays an important role in cell malignant proliferation, but there are still many contradictions in the effect of arsenic on JAK2/STAT3. This study aims to explore the role of JAK2/STAT3 in arsenic-induced cell proliferation. Methods By taking normal cells as the research object and using Standard Mean Difference (SMD) as the effect size, meta-analysis was used to explore the effect of arsenic on JAK2/STAT3. Then, the dose-effect Meta was used to further clarify the dose-effect relationship of arsenic on JAK2/STAT3. Results Through meta-analysis, this study found that arsenic could promote the phosphorylation of STAT3 (SMD=4.21, 95%CI [1.05, 7.37]), and increase IL-6 and p-JAK2, Vimentin, VEGF expression levels, thereby inducing malignant cell proliferation. In addition, this study also found that arsenic exposure dose (<5 μmol m−3), time(<24 h) and cell type were important sources of heterogeneity in the process of exploring the effects of arsenic on p-STAT3, IL-6 and p-JAK2. Dose-effect relationship meta-analysis results showed that arsenic exposure significantly increased the expression level of IL-6. When the arsenic exposure concentration was less than 7 μmol m−3, the expression level of p-JAK2 upregulated significantly as the arsenic exposure concentration gradually increasing. Moreover, the expression level of p-STAT3 elevated significantly with the gradual increase of the arsenic concentration under 5 μmol m−3 of arsenic exposure, but the expression level of p-STAT3 gradually decreases when the concentration is greater than 5 μmol m−3. Conclusions Exposure to low dose of arsenic could promote the expression of JAK2/STAT3 and induce the malignant proliferation of cells through upregulating IL-6, and there was dose-effect relationship among them.

This study investigated the effects of proanthocyanidins (PC) on arsenic methylation metabolism and efflux in human hepatocytes (L-02), as well as the relationships between PC and GSH, MRP1 and other molecules. Cells were randomly divided into blank control group, arsenic trioxide exposure group (ATO, As2O3, 25μmol/L), and PC-treated arsenic exposure group (10, 25, 50mg/L). After 24/48h, the contents of different forms of arsenic were determined, and the methylation indexes were calculated. Intracellular S-adenosyl methionine (SAM), arsenic (+3 oxidation state) methyltransferase (AS3MT), multidrug resistance-associated protein 1 (MRP1), and reduced glutathione (GSH) were ascertained. Changing trends were observed and the correlation between arsenic metabolism and efflux related factors and arsenic metabolites was analyzed. We observed that cells showed increased levels of content/constituent ratio of methyl arsenic, primary/secondary methylation index, methylation growth efficiency/rate, and the difference of methyl arsenic content in cells and culture medium (P<0.05, resp.). Compared with ATO exposure group, the intracellular SAM content in PC-treated group decreased, and the contents of GSH, AS3MT, and MRP1 increased (P<0.05, resp.). There was a positive correlation between the content of intracellular GSH/AS3MT and methyl arsenic. The content of MRP1 was positively correlated with the difference of methyl arsenic content in cell and culture medium; conversely, the SAM content was negatively correlated with intracellular methyl arsenic content (P<0.05, resp.). Taken together, these results prove that PC can promote arsenic methylation metabolism and efflux in L-02 cells, which may be related to the upregulation of GSH, MRP1, and AS3MT levels by PC.