生命早期暴露于环境污染物如砷(As)会增加后代患癌症的风险。在早期的一项研究中,我们表明,只有产前暴露于BALB/c小鼠后代中,表皮干细胞的增殖显着增加并加速皮肤肿瘤发生。在目前的工作中,我们已经研究了As条件真皮成纤维细胞(DFs)在后代角质形成细胞干细胞(KSCs)中的作用。从产前暴露动物中分离的DFs显示出增加的激活标记水平(α-SMA,纤连蛋白,胶原蛋白IV),十一点易位甲基胞嘧啶双加氧酶1(TET1)的诱导,并分泌高水平的生态位修饰IL-6。这导致扩散加剧,迁移,和KSC的存活。通过TET1介导的5-mC向5-hmC转化在其启动子上的-698/-526和-856/-679区来驱动As条件成纤维细胞中IL-6产生的增加。IL-6通过JAK2-STAT3信号的下游激活进一步发挥作用,促进KSC的上皮-间质转化(EMT)。IL-6诱导的pSTAT3的抑制减少了KSC中的EMT过程,导致其增殖的显著降低,迁移,和殖民地的形成。我们的结果表明,产前条件成纤维细胞产生的IL-6在调节As暴露后代的KSC生态位和促进皮肤肿瘤发展中起主要作用。
Early life exposure to environmental pollutants such as arsenic (As) can increase the risk of cancers in the offspring. In an earlier study, we showed that only prenatal As exposure significantly increases epidermal stem cell proliferation and accelerates skin tumorigenesis in BALB/c mouse offspring. In the present work, we have examined the role of As-conditioned dermal fibroblasts (DFs) in creating pro-tumorigenic niches for Keratinocyte stem cells (KSCs) in the offspring. DFs isolated from prenatally exposed animals showed increased levels of activation markers (α-SMA, Fibronectin, Collagen IV), induction of ten-eleven translocation methylcytosine dioxygenase 1(TET1), and secreted high levels of niche modifying IL-6. This led to enhanced proliferation, migration, and survival of KSCs. Increased IL-6 production in As-conditioned fibroblast was driven through TET1 mediated 5-mC to 5-hmC conversion at -698/-526 and -856/-679 region on its promoter. IL-6 further acted through downstream activation of JAK2-STAT3 signaling, promoting epithelial-to-mesenchymal transition (EMT) in KSCs. Inhibition of pSTAT3 induced by IL-6 reduced the EMT process in KSCs resulting in a significant decrease in their proliferation, migration, and colony formation. Our results indicate that IL-6 produced by prenatally conditioned fibroblasts plays a major role in regulating the KSC niche and promoting skin tumor development in As-exposed offspring.