Downregulation of microRNA-515-5p by the Estrogen Receptor Modulates Sphingosine Kinase 1 and Breast Cancer Cell Proliferation

Pinho, Filipa G.; Frampton, Adam E.; Nunes, João; Krell, Jonathan; Alshaker, Heba; Jacob, Jimmy; Pellegrino, Loredana; Roca-Alonso, Laura; Giorgio, Alex de; Harding, Victoria; Waxman, Jonathan; Stebbing, Justin; Pchejetski, Dimitri; Castellano, Leandro

doi:10.1158/0008-5472.can-13-0158

Cited by 70 publications

(65 citation statements)

References 33 publications

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“…However, recently, we identified its role as a tumour suppressor in breast cancer 11. We demonstrated that miR‐515‐5p transcription was directly down‐regulated by the oestrogen receptor and that miR‐515‐5p inhibited breast cell proliferation by inducing apoptosis 11. During this work, a change in MCF‐7 and MDA‐MB‐231 cell morphology was also observed, a finding that we investigate further here.…”

Section: Introductionsupporting

confidence: 57%

“…Both MCF7 and MDA‐MB‐231 cells appeared enlarged with a loss of polarity that is often associated with non‐migratory cells. This change did not correlate with the onset of cell death downstream of this miRNA 11 indicating that the effects of miR‐515‐5p on cell morphology may be caused by distinct targets and, consequently, through different signalling pathways. Additionally, because MDA‐MB‐231 is an ER‐negative breast cancer cell line, we propose that the oestrogen receptor‐α is not involved in these effects.…”

Section: Discussionmentioning

confidence: 92%

“…Initially, we investigated the role of miR‐515‐5p in cell migration because we observed rearrangement of the tubulin cytoskeleton in MCF7 and MDA‐MB‐231 cells that overexpressed miR‐515‐5p (Fig 1A). We previously demonstrated that ERα suppresses miR‐515‐5p expression by direct interaction with its promoter, indicating a link between this miRNA and oestrogen signalling 11. Interestingly, the expression of miR‐515‐5p is lower in MCF7 epithelial‐like cells than in MDA‐MB‐231 which are more mesenchymal‐like.…”

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 98%

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miR‐515‐5p controls cancer cell migration throughMARK4 regulation

et al. 2016

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Here, we show that miR‐515‐5p inhibits cancer cell migration and metastasis. RNA‐seq analyses of both oestrogen receptor receptor‐positive and receptor‐negative breast cancer cells overexpressing miR‐515‐5p reveal down‐regulation of NRAS, FZD4, CDC42BPA, PIK3C2B and MARK4 mRNAs. We demonstrate that miR‐515‐5p inhibits MARK4 directly 3′ UTR interaction and that MARK4 knock‐down mimics the effect of miR‐515‐5p on breast and lung cancer cell migration. MARK4 overexpression rescues the inhibitory effects of miR‐515‐5p, suggesting miR‐515‐5p mediates this process through MARK4 down‐regulation. Furthermore, miR‐515‐5p expression is reduced in metastases compared to primary tumours derived from both in vivo xenografts and samples from patients with breast cancer. Conversely, miR‐515‐5p overexpression prevents tumour cell dissemination in a mouse metastatic model. Moreover, high miR‐515‐5p and low MARK4 expression correlate with increased breast and lung cancer patients' survival, respectively. Taken together, these data demonstrate the importance of miR‐515‐5p/MARK4 regulation in cell migration and metastasis across two common cancers.

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Section: Introductionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 98%

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miR‐515‐5p controls cancer cell migration throughMARK4 regulation

et al. 2016

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“…miRNAs are short approximately 19-24 nucleotide non-coding RNA molecules that post-transcriptionally regulate gene expression via mRNA binding (RNA interference). In cancers, miRNAs have been shown to affect several key oncogenic processes including apoptosis, migration and proliferation (Fonseca-Sanchez et al 2013, Huang et al 2013, Pinho et al 2013. Interestingly, widespread dysregulation of miRNAs has been observed in prostate cancer (Schaefer et al 2010, Fendler et al 2011, Wach et al 2012, and these molecules have potential as both biomarkers and therapeutic targets/treatments (Lichner et al 2013, Maugeri-Sacca et al 2013.…”

Section: Introductionmentioning

confidence: 99%

A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer

Stegeman¹,

Moya²,

Selth³

et al. 2015

Endocrine-Related Cancer

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The oncogene MDM4, also known as MDMX or HDMX, contributes to cancer susceptibility and progression through its capacity to negatively regulate a range of genes with tumoursuppressive functions. As part of a recent genome-wide association study it was determined that the A-allele of the rs4245739 SNP (AOC), located in the 3 0 -UTR of MDM4, is associated with an increased risk of prostate cancer. Computational predictions revealed that the rs4245739 SNP is located within a predicted binding site for three microRNAs (miRNAs): miR-191-5p, miR-887 and miR-3669. Herein, we show using reporter gene assays and endogenous MDM4 expression analyses that miR-191-5p and miR-887 have a specific affinity for the rs4245739 SNP C-allele in prostate cancer. These miRNAs do not affect MDM4 mRNA levels, rather they inhibit its translation in C-allele-containing PC3 cells but not in LNCaP cells homozygous for the A-allele. By analysing gene expression datasets from patient cohorts, we found that MDM4 is associated with metastasis and prostate cancer progression and that targeting this gene with miR-191-5p or miR-887 decreases in PC3 cell viability. This study is the first, to our knowledge, to demonstrate regulation of the MDM4 rs4245739 SNP C-allele by two miRNAs in prostate cancer, and thereby to identify a mechanism by which the MDM4 rs4245739 SNP A-allele may be associated with an increased risk for prostate cancer.Key Words " MDM4" microRNA " single nucleotide polymorphism " prostate cancer

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Relationship between Sphk1/S1P and microRNAs in human cancers

Khoei

Sadeghi

Samadi

et al. 2020

Biotech and App Biochem

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Sphingosine kinases type 1 (SphK1) is a key enzyme in the phosphorylation of sphingosine to sphingosine 1‐phosphate (S1P). Different abnormalities in SphK1 functions may correspond with poor prognosis in various cancers. Additionally, upregulated SphK1/S1P could promote cancer cell proliferation, angiogenesis, mobility, invasion, and metastasis. MicroRNAs as conserved small noncoding RNAs play major roles in cancer initiation, progression, metastasis, etc. Their posttranscriptionally mechanisms could affect the development of cancer growth or tumorigenesis suppression. The growing number of studies has described that various microRNAs can be regulated by SphK1, and its expression level can also be regulated by microRNAs. In this review, the relationship of SphK1 and microRNA functions and their interaction in human malignancies have been discussed. Based on them novel treatment strategies can be introduced.

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Downregulation of microRNA-515-5p by the Estrogen Receptor Modulates Sphingosine Kinase 1 and Breast Cancer Cell Proliferation

Cited by 70 publications

References 33 publications

miR‐515‐5p controls cancer cell migration throughMARK4 regulation

miR‐515‐5p controls cancer cell migration throughMARK4 regulation

A genetic variant of MDM4 influences regulation by multiple microRNAs in prostate cancer

Relationship between Sphk1/S1P and microRNAs in human cancers

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