MiR-15a is underexpressed and inhibits the cell cycle by targeting CCNE1 in breast cancer

Luo, Qifeng; Li, Xiaoyü; Li, Jia; Kong, Xiangjie; Zhang, Junfeng; Chen, Lei; Huang, Yixiang; Fang, Lin

doi:10.3892/ijo.2013.2034

Cited by 84 publications

(59 citation statements)

References 24 publications

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“…Previous reports have also demonstrated that the miR-15a/16-1 miRNA cluster functions as a tumor suppressor, targeting Bcl-2 protein in prostate tumor cells (21)(22)(23)32,33). Inhibition of cell proliferation by miR-15a/16-1 has been reported to occur in both lymphoid and nonlymphoid tissue (21-23,32,33,37,38), Wang et al (40) further demonstrated the miR15a level is increased and it induces cell death in an ischemia reperfusion model (39,41). Our current studies revealed a differential effect of miR-15a/16 on apoptosis in nontumor lung epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA-15a/16 Regulates Apoptosis of Lung Epithelial Cells After Oxidative Stress

Cao

Zhang

Moon

et al. 2016

Mol Med

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Lung epithelial cell apoptosis is an important feature of hyperoxia-induced lung injury. The death receptor-associated extrinsic pathway and mitochondria-associated intrinsic pathway both mediate the development of lung epithelial cell apoptosis. Despite decades of research, molecular mechanisms of hyperoxia-induced epithelial cell apoptosis remain incompletely understood. Here, we report a novel regulatory paradigm in response to hyperoxia-associated oxidative stress. Hyperoxia markedly upregulated microRNA (miR)-15a/16 levels in lung epithelial cells, bronchoalveolar lavage fluid (BALF) and lung tissue. This effect was mediated by hyperoxia-induced reactive oxygen species. Functionally, miR-15a/16 inhibitors induced caspase-3-mediated lung epithelial cell apoptosis, in the presence of hyperoxia. MiR-15a/16 inhibitors robustly enhanced FADD level and downregulated Bcl-2 expression. Consistently, cleaved caspase-8 and -9 were highly induced in the miR-15a/16-deficient cells, after hyperoxia. Using airway epithelial cell-specific, miR-15a/16 -/-mice, we found that Bcl-2 was significantly reduced in lung epithelial cells in vivo after hyperoxia. In contrast, caspase-3, caspase-8 and Bcl-2-associated death promoter (BAD) were highly elevated in the miR-15a/16 -/-epithelial cells in vivo. Interestingly, in lung epithelial malignant cells, rather than benign cells, deletion of miR-15a/16 prevented apoptosis. Furthermore, deletion of miR-15a/16 in macrophages also prohibited apoptosis, which is the opposite of what we have found in normal lung epithelial cells. Taken together, our data suggested that miR-15a/16 may exert differential roles in different cell types. MiR-15a/16 deficiency results in lung epithelial cell apoptosis in response to hyperoxia, via modulating both intrinsic and extrinsic apoptosis pathways.

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Section: Discussionmentioning

confidence: 99%

“…MiR-15a/16 also targets cell cycle regulators. Inhibition of miR-15 expression enhances cyclin E1 mRNA and protein levels (41). Inhibition of both miR-15 and 16 expression augments G 1 /S transition, while overexpression of miR-15 reduces cyclin E protein levels and inhibits the G 1 /S transition (42).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-15a/16 Regulates Apoptosis of Lung Epithelial Cells After Oxidative Stress

Cao

Zhang

Moon

et al. 2016

Mol Med

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“…Luo et al revealed that overexpression of miR-15a inhibited cellular growth, suppressed migration and arrested cells at the G1 phase, but did not promote cellular apoptosis (Luo et al, 2013). Cai et al found that miR-15a downregulate CCND1 and induce apoptosis and cell cycle arrest in osteosarcoma (Cai et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

MiRNA-15a Mediates Cell Cycle Arrest and Potentiates Apoptosis in Breast Cancer Cells by Targeting Synuclein-γ

Xie²,

Chen³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Recent studies have indicated that microRNA-15a (miR-15a) is dysregulated in breast cancer (BC). We aimed to evaluate the expression of miR-15a in BC tissues and corresponding para-carcinoma tissues. We also focused on effects of miR-15a on cellular behavior of MDA-MB-231 and expression of its target gene synuclein-γ (SNCG). Materials and Methods: The expression levels of miR-15a were analysed in BC formalin fixed paraffin embedded (FFPE) tissues by microarray and quantitative real-time PCR. CCK-8 assays, cell cycle and apoptosis assays were used to explore the potential functions of miR-15a in MDA-MB-231 human BC cells. A luciferase reporter assay confirmed direct targets. Results: Downregulation of miR-15a was detected in most primary BCs. Ectopic expression of miR-15a promoted proliferation and suppressed apoptosis in vivo. Further studies indicated that miR-15a may directly interact with the 3'-untranslated region (3'-UTR) of SNCG mRNA, downregulating its mRNA and protein expression levels. SNCG expression was negatively correlated with miR-15a expression. Conclusions: MiR-15a has a critical role in mediating cell cycle arrest and promoting cell apoptosis of BC, probably by directly targeting SNCG. Thus, it may be involved in development and progression of BC.

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“…In this regard, it has been shown that HER2Δ16 (a clinically important oncogenic isoform of HER2) can suppresses miR-15a (Cittelly et al, 2010). In addition, miR-15a was shown to mediate cell cycle arrest and promoting cell apoptosis of breast cancer by directly targeting Cyclin E1 suggesting the tumor suppressive activity of miR-15a in a breast cancer cell line (Luo et al, 2013;Shinden et al, 2015). Moreover, the identification of HER2/neu-induced miR-15a repression provides a greater understanding into how HER2/neu overexpression promotes invasion and significantly differentially expressed miR-335 and miR-24 upon non-IBC groups based on menopausal status and miR-342-5p based on parity profile; B) the fold change of the significantly differentially expressed miR-15a and miR-24 upon IBC groups according to HER-2 and menopausal status respectively.…”

Section: Discussionmentioning

confidence: 99%

Circulating Cell-free miRNA Expression and its Association with Clinicopathologic Features in Inflammatory and Non-Inflammatory Breast Cancer

Hamdi¹,

Blancato²,

Goerlitz³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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Recent discovery showing the presence of microRNAs (miRNAs) in the circulation sparked interest in their use as potential biomarkers. Our previous studies showed the diagnostic potential of miR-451 as a serological marker for inflammatory breast cancer (IBC), miR-337-5p and miR-30b for non-inflammatory breast cancer (non-IBC). The aim of this study is to investigate the prognostic values of circulating miRNAs by comparing the amounts of 12 circulating miRNAs in the serum of IBC and non-IBC from Tunisian breast cancer patients, and by determinating whether correlated pairs of miRNAs could provide useful information in the diagnosis of IBC and non-IBC patients. TaqMan qPCR was performed to detect circulating expression of miRNAs in serum of 20 IBC, 20 non-IBC and 20 healthy controls. Nonparametric rank Spearman rho correlation coefficient was used to examine the prognostic value of miRNAs and to assess the correlation profile between miRNAs expression. Further, a large number of miRNAs were highly correlated (rho>0.5) in both patients groups and controls. Also, the correlations profiles were different between IBC, non-IBC and healthy controls indicating important changes in molecular pathways in cancer cells. Our results showed that miR-335 was significantly overexpressed in premenopausal non-IBC patients; miR-24 was significantly overexpressed in non-IBC postmenopausal patients. Patients with previous parity had higher serum of miR-342-5p levels than those without. Furthermore, patients with HER2+ IBC present lower serum levels of miR-15a than patients with HER2-disease. Together, these results underline the potential of miRNAs to function as diagnostic and prognostic markers for IBC and non-IBC, with links to the menopausal state, Her2 status and parity.

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MiR-15a is underexpressed and inhibits the cell cycle by targeting CCNE1 in breast cancer

Cited by 84 publications

References 24 publications

MicroRNA-15a/16 Regulates Apoptosis of Lung Epithelial Cells After Oxidative Stress

MicroRNA-15a/16 Regulates Apoptosis of Lung Epithelial Cells After Oxidative Stress

MiRNA-15a Mediates Cell Cycle Arrest and Potentiates Apoptosis in Breast Cancer Cells by Targeting Synuclein-γ

Circulating Cell-free miRNA Expression and its Association with Clinicopathologic Features in Inflammatory and Non-Inflammatory Breast Cancer

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