Abstract
The epithelial-to-mesenchymal (EMT) transition is a prerequisite for conferring metastatic potential during tumor progression. microRNA-30a (miR-30a) expression was significantly lower in aggressive breast cancer cell lines compared with non-invasive breast cancer and non-malignant mammary epithelial cell lines. In contrast, miR-30a overexpression reversed the mesenchymal appearance of cancer cells to result in a cobblestone-like epithelial phenotype. We identified Slug, one of the master regulators of EMT, as a target of miR-30a using in silico prediction. Reporter assays indicated that miR-30a could bind to the 3′-untranslted region of Slug mRNA. Furthermore, we linked miR-30a to increased expression of claudins, a family of tight junction transmembrane proteins. An interaction between Slug and E-box in the claudin promoter sequences was reduced upon miR-30a overexpression, further leading to reduction of filopodia formation and decreased invasiveness/metastasis capabilities of breast cancer cells. Consistently, delivery of miR-30a in xenografted mice decreased tumor invasion and migration. In patients with breast cancer, a significantly elevated risk of the miR-30alow/CLDN2low/FSCNhigh genotype was observed, linking to a phenotypic manifestation of larger tumor size, lymph node metastasis, and advanced tumor stage among patients. In conclusion, the miR-30a/Slug axis inhibits mesenchymal tumor development by interfering with metastatic cancer cell programming and may be a potential target for therapy in breast cancer.
Highlights
The epithelial-to-mesenchymal transition (EMT) enables tumor cells to transiently lose their epithelial features—including the loss of apico-basal polarity and disassembly of tight and adherent junctions—and acquire mesenchymal traits that lead to invasion, metastasis, and resistance to chemotherapy [1, 2]
Because these two cell lines are intrinsically deficient in expression of E-cadherin [11], which is a key protein contributing to cell-cell adhesion, we hypothesized that miR-30a targets other mRNAs involved in regulating EMT
We first assessed whether decreased miR-30a expression was significantly associated with breast cancer aggressiveness in different breast cancer cell lines. miR-30a levels were significantly decreased in highly aggressive Hs578T and MDA-MB-231 breast cancer cell lines as compared with a moderate decrease in non-invasive MCF-7 and BT-474 breast cancer cell lines and in non-malignant mammary epithelial cell lines H184B5F5/M10 and MCF-10A (Figure 1A)
Summary
The epithelial-to-mesenchymal transition (EMT) enables tumor cells to transiently lose their epithelial features—including the loss of apico-basal polarity and disassembly of tight and adherent junctions—and acquire mesenchymal traits that lead to invasion, metastasis, and resistance to chemotherapy [1, 2]. A growing body of research has indicated that cancer cells acquire the ability to invade and disseminate via the action of dysregulated miRNAs that enhance EMT progression [6, 7] and confer a selective advantage during clonal evolution [8, 9]. Our previous breast cancer study revealed that miR-30a inhibits the invasion and migration of Hs578T and MDA-MB-231 breast cancer cells in vitro [10]. Because these two cell lines are intrinsically deficient in expression of E-cadherin [11], which is a key protein contributing to cell-cell adhesion, we hypothesized that miR-30a targets other mRNAs involved in regulating EMT
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