Yu Jing, Li Qi, Xu Qing, Liu Lingzhi, Jiang Binghua
Lab of Reproductive Medicine, Department of Pathology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, Jiangsu 210029, China;
J Biomed Res. 2011 May;25(3):170-7. doi: 10.1016/S1674-8301(11)60022-5.
MicroRNAs (miRNAs) play an important role in carcinogenesis in various solid cancers including breast cancer. Down-regulation of microRNA-148a (miR-148a) has been reported in certain cancer types. However, the biological role of miR-148a and its related targets in breast cancer are unknown yet. In this study, we showed that the level of miR-148a was lower in MCF7 cells than that in MCF10A cells. V-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3) is a direct target of miR-148a in human breast cancer cells through direct binding of miR-148a to ERBB3 3'-UTR region. Overexpression of miR-148a in MCF7 cells inhibited ERBB3 expression, blocked the downstream pathway activation including activation of AKT, ERK1/2, and p70S6K1, and decreased HIF-1α expression. Furthermore, forced expression of miR-148a attenuated tumor angiogenesis in vivo. Our results identify ERBB3 as a direct target of miR-148a, and provide direct evidence that miR-148a inhibits tumor angiogenesis through ERBB3 and its downstream signaling molecules. This information would be helpful for targeting the miR-148a/ERBB3 pathway for breast cancer prevention and treatment in the future.
微小RNA（miRNA）在包括乳腺癌在内的多种实体癌的致癌过程中发挥着重要作用。在某些癌症类型中，已报道微小RNA - 148a（miR - 148a）表达下调。然而，miR - 148a及其相关靶点在乳腺癌中的生物学作用尚不清楚。在本研究中，我们发现MCF7细胞中miR - 148a的水平低于MCF10A细胞。V - erb - b2成红细胞白血病病毒癌基因同源物3（ERBB3）是miR - 148a在人乳腺癌细胞中的直接靶点，通过miR - 148a与ERBB3 3'-非翻译区直接结合。在MCF7细胞中过表达miR - 148a可抑制ERBB3表达，阻断包括AKT、ERK1/2和p70S6K1激活在内的下游通路激活，并降低HIF - 1α表达。此外，强制表达miR - 148a可在体内减弱肿瘤血管生成。我们的结果确定ERBB3是miR - 148a的直接靶点，并提供了直接证据表明miR - 148a通过ERBB3及其下游信号分子抑制肿瘤血管生成。这一信息将有助于未来针对miR - 148a/ERBB3通路进行乳腺癌的预防和治疗。
