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LincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6.

ABSTRACT: Triple-negative (ER(-), HER2(-), PR(-)) breast cancer (TNBC) is an aggressive disease with a poor prognosis with no available molecularly targeted therapy. Silencing of microRNA-145 (miR-145) may be a defining marker of TNBC based on molecular profiling and deep sequencing. Therefore, the molecular mechanism behind miR-145 downregulation in TNBC was examined. Overexpression of the long intergenic noncoding RNA regulator of reprogramming, lincRNA-RoR, functions as a competitive endogenous RNA sponge in TNBC. Interestingly, lincRNA-RoR is dramatically upregulated in TNBC and in metastatic disease and knockdown restores miR-145 expression. Previous reports suggest that miR-145 has growth-suppressive activity in some breast cancers; however, these data in TNBC indicate that miR-145 does not affect proliferation or apoptosis but instead, miR-145 regulates tumor cell invasion. Investigation of miR-145-regulated pathways involved in tumor invasion revealed a novel target, the small GTPase ADP-ribosylation factor 6 (Arf6). Subsequent analysis demonstrated that ARF6, a known regulator of breast tumor cell invasion, is dramatically upregulated in TNBC and in breast tumor metastasis. Mechanistically, ARF6 regulates E-cadherin localization and affects cell-cell adhesion. These results reveal a lincRNA-RoR/miR-145/ARF6 pathway that regulates invasion in TNBCs.The lincRNA-RoR/miR-145/ARF6 pathway is critical to TNBC metastasis and could serve as biomarkers or therapeutic targets for improving survival.

SUBMITTER: Eades G

PROVIDER: S-EPMC4336811 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6.

Eades Gabriel G Wolfson Benjamin B Zhang Yongshu Y Li Qinglin Q Yao Yuan Y Zhou Qun Q

Molecular cancer research : MCR 20140924 2

<h4>Unlabelled</h4>Triple-negative (ER(-), HER2(-), PR(-)) breast cancer (TNBC) is an aggressive disease with a poor prognosis with no available molecularly targeted therapy. Silencing of microRNA-145 (miR-145) may be a defining marker of TNBC based on molecular profiling and deep sequencing. Therefore, the molecular mechanism behind miR-145 downregulation in TNBC was examined. Overexpression of the long intergenic noncoding RNA regulator of reprogramming, lincRNA-RoR, functions as a competitive ...[more]

PMID: 25253741

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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.

Project description:BackgroundLong non-coding RNAs (lncRNAs) are a class of non-protein coding RNAs greater than 200 nucleotides (nt) in length which have been shown to be significantly highly expressed in the heart tissue of mice undergoing thoracic aortic arch constriction (TAC). Micro RNAs (miRNAs) are a class of non-protein-coding RNAs. Many miRNAs have been reported to play a key role in the progression of myocardial hypertrophy. In this study, we aimed to investigate whether lncRNA reprogramming regulators (ROR) promotes hypoxic injury in cardiomyocytes by targeting and regulating the miR-145/HS1-associated protein X-1 (HAX-1) axis.MethodsA mouse model of myocardial hypertrophy was established by conventional TAC method, and the cardiomyocytes were isolated. We transfected pcDNA3.0-ROR vector, pcDNA3.0-HAX-1 vector plasmid, and miR-145 simulant into cardiomyocytes with Lipofectamine 2000. Luciferase reporter gene was used to analyze the targeting relationship between genes.ResultsThe expression of ROR in hypertrophic myocardium was significantly increased after phenylephrine (PE) intervention. After transfection with si-ROR, the ROR expression in hypertrophic cardiomyocytes treated with PE decreased significantly. Levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), creatine kinase (CK) decreased and superoxide dismutase (SOD) increased. The expression of miR-145 in cardiomyocytes was significantly down-regulated after PE treatment. In hypertrophic cardiomyocytes, after up-regulating the expression of miR-145, the relative messenger ribonucleic acid (mRNA) and protein expressions of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) induced by PE decreased. Compared with the miR-NC group, wild type (WT)-ROR activity in the miR-145 group was significantly inhibited (P<0.05), and mutant (MUT)-ROR activity had no significant change (P>0.05). When cardiomyocytes were transfected with HAX-1 3'URT WT vector along with miR-145 simulant, miR-145 inhibitor, and their respective controls. Compared with the control groups, the luciferase activity of cells transfected with simulant was significantly decreased (P<0.05), and increased in inhibitor group (P<0.05). Transfection of HAX-1 3'URT mutant vector did not show this phenomenon. ROR was negatively correlated with miR-145 expression and positively correlated with HAX-1 mRNA.ConclusionsThe lncRNA ROR can promote the expression of HAX-1 by competitive binding with miR-145, so as to promote the pathophysiological process of myocardial hypertrophy.

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LincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6.

Publications

lincRNA-RoR and miR-145 regulate invasion in triple-negative breast cancer via targeting ARF6.

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