Abstract
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.
Highlights
Breast cancer is the most common cancer in women with more than 400,000 deaths each year worldwide
To determine whether the expression of miR-148a is downregulated in breast cancer cells, human breast cancer cell lines MCF7 and T47D and the immortalized normal breast epithelial cells MCF10A were used to test the levels of miR-148a by TaqMan realtime RT-PCR analysis
This result shows that miR-148a inhibits ERBB3 wild type reporter activities through the binding of miR-148a in the seed region. These results demonstrate that ERBB3 is a direct target of miR-148a in breast cancer cells
Summary
Breast cancer is the most common cancer in women with more than 400,000 deaths each year worldwide. MicroRNAs (miRNAs) are a class of small noncoding RNAs that have been identified as a new kind of gene expression regulators through targeting the 3’-untranslated region (UTR) of mRNAs for translational repression or degradation[1,2]. MiRNAs are differentially expressed in various human cancers, functioning either as oncogenes or tumor suppressors by controlling the expression of their target genes[3,4]. Some miRNAs were related to cancer biopathological features like vascular invasion, lymph node metastasis, tumor stage and cell proliferation[3,4,5]. The hypermethylation-associated miR-148a silencing has been reported to be correlated with human cancer metastasis[10]. Overexpression of miR-148a attenuated paclitaxel resistance of hormone-refractory, drug-resistant prostate cancer PC3 cells by regulating mitogen- and stress-activated kinase 1 (MSK1) expression[11].
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