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  • Furthermore the determination of downstream target genes


    Furthermore, the determination of downstream target genes induced by CdCl2 is noteworthy and can help to define its underlying carcinogenesis mechanism. Therefore, we evaluated c-fos and c-jun expression which are stimulated by estrogen through ERK/MAPK pathway. These are not only proto-oncogenes which in combination together act as the transcription factor and regulate cell proliferation but also are key components which are activated by mitogenic stimuli and play an important role in many cellular functions to convert extracellular signals to change of gene expression (Adams et al., 2014). Estrogen can stimulate c-fos and c-jun through ERK pathway. We demonstrated that c-fos and c-jun mRNA expression were up-regulated by CdCl2 similar to E2. Cd effects on c-fos and c-jun expression can be mediated by ER involvement. Ronchetti showed that 10 nM Cd enhanced c-fos mRNA expression in an ERα − dependent manner in anterior pituitary cells (Ronchetti et al., 2013). Some data indicated that Cd increased cell proliferation by stimulation of ERK1/2 activity probably through activation of c-fos, c-jun and by an ERα-dependent mechanism (Brama et al., 2007; Roskoski, 2012). Additionally, our analysis demonstrated that cells exposed to Cd also expressed higher levels of FOXO3a compared to control. This gene is a member of FOXO proteins which regulates KPT-335 mg and modulates progression of cells. Some studies reported that FOXO3a expression correlated with some clinical responses of breast cancer such as ER positivity, axillary lymph node negativity and histologic grade (Esteva et al., 2002; Jiang et al., 2013). Recent studies suggested a clear link between the expression of FOXO3a and ER+ in breast cancer (Guo and Sonenshein, 2004; Jiang et al., 2013). Guo and Sonenshein postulated that overexpression of FOXO3a increased expression of ERα in ERα + NF639 and T47D cells. They identified two strongly binding forkhead sites in ERα promoter and introduced FOXO3a as a key mediator of expression of ERα in breast cancer (Guo and Sonenshein, 2004; Madureira et al., 2006). Furthermore, it is also regulated by the ERK/MAPK pathway (Myatt and Lam, 2007). These results showed that Cd exposure induced the expression of FOXO3a through ERK1/2 signaling pathway and suggested that FOXO3a might regulate cell proliferation in Cd-exposed ovarian cells. Finally, it would be intriguing to design a model of the possible mechanism by which CdCl2 activated intracellular signaling cascade in ovarian cancer cell proliferation in Fig. 8. CdCl2 induced the proliferation of the ovarian cancer cells and expression of ER in an ER-dependent manner by increasing p-ERK1/2 and following activation of c-fos, c-jun, and FOXO3a transcription factors.
    Conflict of interest
    Acknowledgement This work was supported by Isfahan University of Medical Sciences, Iran (Grant number 394160).
    Introduction Zearalenone (ZEA), chemically described as 6-(10-hydroxy-6-oxo-trans-1-undecenyl)-β-resocyclic acid lactone, is one of the well-known mycotoxins produced by Fusarium species, whose contamination is present world-wide (W. Zheng et al., 2018). Human and animal exposure to ZEA is mainly associated with consumption of feed and food products derived from contaminated cereals, both during the process of growth as well as the storage (W.-L Zheng et al., 2018). The recent reports present that ZEA could trigger different toxicity mechanisms at different doses and cell types (Yip et al., 2017). Nevertheless, its toxicity is mainly associated with long-term exposure and involves endocrine-disrupting effects in animals: alteration of the production of sex hormones, disturbances in fertility as well as premature births in domestic animals (Kowalska et al., 2016). Due to the fact that ZEA is also one of the Endocrine Disruptor Chemicals (EDC), it is possible that it might disturb the hormonal balance in humans (Kowalska et al., 2016). On the one hand, ZEA induces oxidative stress, causes DNA damage, modulates cell cycle progression and trigger apoptosis and autophagy in cells (Lin et al., 2015, Yang et al., 2018). On the other hand, ZEA is reported to increase the proliferation of cells, promotes cell migration and invasion (Kowalska et al., 2018, Zheng et al., 2018a, Zheng et al., 2018b). The pro-carcinogenic effect of ZEA is reported to be mainly associated with the estrogen-like structure of ZEA, as well as studies which documented that ZEA influences the estrogen-dependent signaling pathways (Kowalska et al., 2018).