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A Novel Bioengineered miR-127 Prodrug Suppresses the Growth and Metastatic Potential of Triple-Negative Breast Cancer Cells.

ABSTRACT: miR-127 is downregulated in breast cancer, where it has been shown to suppress the proliferation, migration, and invasion of breast cancer cells. In triple-negative breast cancer (TNBC), miR-127 downregulation correlates with decreased disease-free and overall patient survival. Tumor suppressor miRNAs may hold therapeutic promise but progress has been limited by several factors, including the lability and high cost of miRNA mimics. Here, we take a novel approach to produce a miR-127 prodrug (miR-127PD), which we demonstrate is processed to mature, functional miR-127-3p in TNBC tumor cells. miR-127PD decreased the viability and motility of TNBC cells, sensitized TNBC cells to chemotherapy, and restricted the TNBC stem cell population. Furthermore, systemic delivery of miR-127PD suppressed tumor growth of MDA-MB-231 and MDA-MB-468 TNBC cells and spontaneous metastasis of MDA-MB-231 cells. In addition, CERK, NANOS1, FOXO6, SOX11, SOX12, FASN, and SUSD2 were identified as novel, functionally important targets of miR-127. In conclusion, our study demonstrates that miR-127 functions as a tumor and metastasis suppressor in TNBC and that delivery of miR-127 may hold promise as a novel therapy. SIGNIFICANCE: Exogenous administration of miR-127, which is functionally activated in target cells, inhibits growth and spontaneous metastasis of triple-negative breast cancer.

SUBMITTER: Umeh-Garcia M

PROVIDER: S-EPMC7002233 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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A Novel Bioengineered miR-127 Prodrug Suppresses the Growth and Metastatic Potential of Triple-Negative Breast Cancer Cells.

Umeh-Garcia Maxine M Simion Catalina C Ho Pui-Yan PY Batra Neelu N Berg Anastasia L AL Carraway Kermit L KL Yu Aiming A Sweeney Colleen C

Cancer research 20191106 3

miR-127 is downregulated in breast cancer, where it has been shown to suppress the proliferation, migration, and invasion of breast cancer cells. In triple-negative breast cancer (TNBC), miR-127 downregulation correlates with decreased disease-free and overall patient survival. Tumor suppressor miRNAs may hold therapeutic promise but progress has been limited by several factors, including the lability and high cost of miRNA mimics. Here, we take a novel approach to produce a miR-127 prodrug (miR ...[more]

PMID: 31694904

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Project description:BackgroundTriple-negative breast cancer (TNBC) is the malignancy with the worst outcome among all breast cancer subtypes. We reported that ETV1 is a significant oncogene in TNBC tumourigenesis. Consequently, investigating the critical regulatory microRNAs (miRNAs) of ETV1 may be beneficial for TNBC targeted therapy.MethodsWe performed in situ hybridization (ISH) and immunohistochemistry (IHC) to detect the location of miR-17-5p and ETV1 in TNBC patient samples, respectively. miR-17-5p expression in TNBC tissues and cell lines was assessed by quantitative real-time PCR (qRT-PCR). ETV1 expression was evaluated by qRT-PCR, western blotting and IHC. Cell Counting Kit-8 (CCK-8), colony formation, Transwell and wound closure assays were utilized to determine the TNBC cell proliferation and migration capabilities. In vivo tumour metastatic assays were performed in a zebra fish model.ResultsThe abundance of miR-17-5p was significantly decreased in TNBC cell lines and clinical TNBC tissues. The miR-17-5p expression levels were closely correlated with tumour size (P < 0.05) and TNM stage (P < 0.05). By contrast, the expression of ETV1 was significantly up-regulated in TNBC cell lines and tissues. There is an inverse correlation between the expression status of miR-17-5p and ETV1 (r = -0.28, P = 3.88 × 10-3). Luciferase reporter assay confirmed that ETV1 was a direct target of miR-17-5p. Forced expression of miR-17-5p in MDA-MB-231 or BT549 cells significantly decreased ETV1 expression and suppressed cell proliferation, migration in vitro and tumour metastasis in vivo. However, rescuing the expression of ETV1 in the presence of miR-17-5p significantly recovered the cell phenotype. High miR-17-5p expression was associated with a significantly favourable prognosis, in either the ETV1-positive or ETV1-negative groups (log-rank test, P < 0.001; P < 0.001). Both univariate and multivariate analyses showed that miR-17-5p and ETV1 were independent risk factors in the prognosis of TNBC patient.ConclusionsOur data indicate that miR-17-5p acts as a tumour suppressor in TNBC by targeting ETV1, and a low-abundance of miR-17-5p may be involved in the pathogenesis of TNBC. These findings indicate that miR-17-5p may be a therapeutic target for TNBC.

Dataset Information

A Novel Bioengineered miR-127 Prodrug Suppresses the Growth and Metastatic Potential of Triple-Negative Breast Cancer Cells.

Publications

A Novel Bioengineered miR-127 Prodrug Suppresses the Growth and Metastatic Potential of Triple-Negative Breast Cancer Cells.

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