The present study analyzed the dose-dependent cyto- and genotoxicity of graphene oxide and reduced graphene oxide on spermatogonial stem cells (SSCs) for the first time. The results showed that graphene oxide significantly increased oxidative stress at concentrations of 100 and 400μg/ml, while low concentrations did not have a significant effect. In addition, according to the MTT assay, the cell number decreased in high-concentration (100 and 400μg/ml) graphene oxide-treated samples compared to untreated cells. However, a reduced graphene-treated sample demonstrated a significant increase in cell number. Moreover, microscopic analysis found high concentrations of graphene nanosheets in cell culture medium that reduced the number of colonies and colony forming cells. We conclude that a high concentration of graphene can be toxic to SSCs. However, such toxicity can be reduced by the surface modification of graphene nanomaterials.

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Epithelial–mesenchymal transition (EMT) is a biological event, which critically regulates migration and invasion of cancer cells. EMT is regulated by several protein and nonprotein factors (such as noncoding RNAs). HOTAIR is an oncogenic long noncoding RNA that stimulates EMT in cancers. In the current study, we investigated the effect of metformin on EMT behavior and HOTAIR expression in MDA‐MB‐231 breast cancer cells. The minimal effective concentrations of metformin (10 and 20 mM) were obtained by the MTT test. Cell migration and invasion in the metformin‐containing medium were assayed in the scratch assay and transwell test. Meaningful decreases in both cell migration and invasion were observed in the presence of metformin. Vimentin, snail, β‐catenin, and HOTAIR transcripts were quantified by real‐time polymerase chain reaction (PCR). Reduction in the expression of vimentin, β‐catenin, and HOTAIR was detected as the result of metformin treatment, but the snail showed a constant expression. Western blottingrevealed the downregulation of vimentin and β‐catenin proteins. HOTAIR promoter methylation pattern was also investigated in metformin‐exposed cells using bisulfite sequencing PCR which the result showed differences in the methylation profile of CpG islands between the treated and untreated cells. In conclusion, metformin modulated oncogenic expression of the HOTAIR gene in the MDA‐MB‐231 cells. This downregulation was associated with the modification of promoter methylation patterns. Since HOTAIR induces EMT in breast cancer, HOTAIR decline might be one of the mechanisms by which metformin reverses EMT.

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