Abstract
MicroRNA-34a (miR-34a) plays an essential role against tumorigenesis and progression of cancer metastasis. Here, we analyzed the expression, targets and functional effects of miR-34a on epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs), such as TWIST1, SLUG and ZEB1/2, and an EMT-inducing protein NOTCH1 in breast cancer (BC) cell migration and invasion and its correlation with tumorigenesis and clinical outcomes. Expression of miR-34a is downregulated in human metastatic breast cancers (MBC) compared to normal breast tissues and is negatively correlated with clinicopathological features of MBC patients. Ectopic expression of miR-34a in MBC cell-line BT-549 significantly inhibits cell migration and invasion, but exhibits no clear effect on BC cell growth. We found that miR-34a is able to inactivate EMT signaling pathway with mediatory of NOTCH1, TWIST1, and ZEB1 upon 3′-UTR activity in MBC cell lines, but has no inhibitory effects on SLUG and ZEB2. Furthermore, we investigated the synergistic effects of Thymoquinone (TQ) and miR-34a together on the expression of EMT-associated proteins. Results showed that co-delivery of miR-34a and TQ is able to inactivate EMT signaling pathway by directly targeting TWIST1 and ZEB1 in BT-549 cell line, indicating that they might be a promising therapeutic combination against breast cancer metastasis. Epigenetic inactivation of the EMT-TFs/miR-34a pathway can potentially alter the equilibrium of these regulations, facilitating EMT and metastasis in BC. Altogether, our findings suggest that miR-34a alone could serve as a potential therapeutic agent for MBC, and together with TQ, their therapeutic potential is synergistically enhanced.
Highlights
From historical to contemporary science, metastatic breast cancers (MBC) have become one of the deadliest female malignancies worldwide with >41,000 deaths per year [1, 2]
We found that miR-34a is able to inactivate epithelial to mesenchymal transition (EMT) signaling pathway with mediatory of Notch homolog 1 (NOTCH1), Twist-related protein 1 (TWIST1), and ZEB1 upon 3′-untranslated region (UTR) activity in MBC cell lines, but has no inhibitory effects on zinc finger protein SNAI2 (SLUG) and ZEB2
The above data showed that miR-34a is significantly downregulated in MBC tissues, suggesting that the downregulation of miR-34a most likely affects the progression of MBC
Summary
From historical to contemporary science, metastatic breast cancers (MBC) have become one of the deadliest female malignancies worldwide with >41,000 deaths per year [1, 2]. Despite significant progresses in clinical treatment strategies of MBC, the 5-year survival rate after curative resection is reported to be only ~24% [3]. Chemotherapy, radiotherapy and molecularly targeted therapy are the main components of MBC therapy [4]. The clinically heterogeneous nature of MBC relatively arises from its biological and genetic heterogeneity. A variety of genetic and epigenetic abnormalities characterizes the development of the metastatic process, where epithelial to mesenchymal transition (EMT) plays a vital, supportive role for local invasion, migration, growth, and drug resistance of breast cancer (BC) cells [6, 7]
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