MicroRNA-93 regulates NRF2 expression and is associated with breast carcinogenesis
MicroRNA-93 regulates NRF2 expression and is associated with breast carcinogenesis
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DOI：
10.1093/carcin/bgt026
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发表时间：
2013-05-01
期刊：
影响因子：
4.7
通讯作者：
Bhat, Hari K.
中科院分区：
文献类型：
--
作者：
Singh, Bhupendra;Ronghe, Amruta M.;Bhat, Hari K.
microRNA（miRNA）是一类小的非编码RNA，调控着人类基因的表达，在疾病过程中起着重要作用。最近的研究表明，表达失调的miRNA和乳腺癌之间的联系。长期雌激素暴露与人类乳腺癌的发展有关，但其潜在机制仍然难以捉摸。我们最近已经证明，抗氧化剂维生素C（维生素C）可以预防雌激素诱导的乳腺肿瘤的发展。在这项研究中，我们研究了维生素C在大鼠乳腺癌发生模型中对microRNA-93（miR-93）及其靶基因的调控作用。雌性8月哥本哈根爱尔兰（ACI）大鼠与维生素C的存在或不存在的17-雌二醇（E2）8个月。我们证明了E2处理的乳腺组织和人乳腺细胞系中miR-93的表达增加，维生素C处理逆转了E2介导的miR-93水平的增加。miRNA靶点预测程序提示miR-93的靶基因之一是核因子红细胞2相关因子2（NRF 2）。与miR-93表达相反，NRF 2蛋白表达在E2处理的乳腺组织、乳腺肿瘤和乳腺癌细胞系中显著降低，并且其表达在维生素C处理后显著增加。miR-93的异位表达降低了NRF 2和NRF 2调节基因的蛋白表达。此外，miR-93减少了乳腺上皮细胞的凋亡，增加了集落形成，乳腺球形成，细胞迁移和DNA损伤，而这些细胞中miR-93的沉默抑制了这些致癌过程。综上所述，我们的研究结果表明miR-93在E2诱导的乳腺癌发生过程中具有致癌潜力。
MicroRNAs (miRNA) are small non-coding RNAs that regulate the expression of approximately 60% of all human genes and play important roles in disease processes. Recent studies have demonstrated a link between dysregulated expression of miRNAs and breast carcinogenesis. Long-term estrogen exposure is implicated in development of human breast cancers, yet underlying mechanisms remain elusive. We have recently demonstrated that antioxidant vitamin C (vit C) prevents estrogen-induced breast tumor development. In this study, we investigated the role of vit C in the regulation of microRNA-93 (miR-93) and its target gene(s) in a rat model of mammary carcinogenesis. Female August Copenhagen Irish (ACI) rats were treated with vit C in the presence or absence of 17-estradiol (E2) for 8 months. We demonstrate an increased expression of the miR-93 in E2-treated mammary tissues and in human breast cell lines and vit C treatment reverted E2-mediated increase in miR-93 levels. MiRNA target prediction programs suggest one of the target genes of miR-93 to be nuclear factor erythroid 2-related factor 2 (NRF2). In contrast with miR-93 expression, NRF2 protein expression was significantly decreased in E2-treated mammary tissues, mammary tumors, and in breast cancer cell lines, and its expression was significantly increased after vit C treatment. Ectopic expression of miR-93 decreased protein expression of NRF2 and NRF2-regulated genes. Furthermore, miR-93 decreased apoptosis, increased colony formation, mammosphere formation, cell migration and DNA damage in breast epithelial cells, whereas silencing of miR-93 in these cells inhibited these carcinogenic processes. Taken together, our findings suggest an oncogenic potential of miR-93 during E2-induced breast carcinogenesis.