Recent studies indicated that BPA can increase the progression of HA via induction of EMT and upregulation of Snail (Zhai et al., 2016). Our present study found that BPS, the “safety” analog of BPA, can trigger the proliferation of HA cells and its cell cycle transition via upregulation of bFGF. Further, BPS can increase the mRNA stability of bFGF via decreasing the expression of miR-155-5p. As well, BPS can increase the transcription of bFGF via activation of NF-κB.
BPS have existed estrogenic and cellular functions in many recent studies (Chin et al., 2018; Kinch et al., 2015; LaPlante et al., 2017). As to cell proliferation, BPS significantly promoted the proliferation of ERα positive MCF-7 cells, but failed to promote the proliferation of ERα negative MDA-MB-231 and SK-BR-3 cells (Lin et al., 2019), which was consistent with our present study that BPS at nanomolar can significantly promote proliferation of HA cells. Our results also observed that BPA can increase S phase and decrease G0/G1 phase of HA cell, which was also consistent with previous data that EDCs such as BPA(Wu et al., 2012), Perfluorooctanoic acid (PFOA) (Pierozan et al., 2018), and polybrominated diphenyl ethers (Li et al., 2012) can reduce the percentage of cells at G0/G1 phase and increase percentage of cells at S phase to trigger the cell cycle transition and cell proliferation. In MCF-7 cells, BPS treatment also resulted in an acceleration of G1-S phase transition (Lin et al., 2019). Since BPS existed comparable estrogenic potency to E2 (Vinas and Watson, 2013) and HA cells can be exposed to BPS via blood circulation, the potential effects of BPS on HA progression need further study.
We found the upregulation of bFGF was involved in BPS induced proliferation of HA cells. The expression of bFGF and its receptor are closely associated with proliferation of infantile cutaneous hemangioma (Przewratil et al., 2010). In situ hybridization and immunohistochemical analysis confirmed that the expression of bFGF is closely correlated with incidence of hemangioma (Bielenberg et al., 1999). The bFGF is an effective stimulator of breast epithelial cells proliferation and differentiation (Korah et al., 2000). Our present study found that the neutralization antibody against bFGF can suppress the proliferation of HA cells and block promotion effect of BPS on cells proliferation, which further confirmed the essential roles of bFGF in HA progression.
We found that activation of p65 and down regulation of miR-155-5p were responsible for BPS induced transcription and upregulation mRNA stability of bFGF, respectively, in HA cells. In bovine mammary epithelial cells (BMEC), the expression of bFGF is dependent on the NF-κB and AP-1 signaling pathways (Wu et al., 2018). While BPS had no significant effect on the phosphorylation of AP1 in HA cells. Further, activation of p65 was also involved in BPA induced migration of cervical cancer cells (Ma et al., 2015). In male zebrafish, BPS exposure can change the expression of 14 miRNAs involved in hematopoiesis, lymphoid organ development, and immune system development (Lee et al., 2018). In pheochromocytoma PC12 cells, BPS can regulate the expression of miR-10b to inhibit the expression of KLF4 and induce cell migration (Jia et al., 2018). It has been reported that miR-15a (Zhu et al., 2017), miR-146a (Liu et al., 2016), and miR-195 (Wang et al., 2017) can also regulate the mRNA stability and expression of bFGF. Whether these miRNAs are involved in BPS regulated expression of bFGF needs further study.