miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels

Abdelmohsen, Kotb; Srikantan, Subramanya; Kuwano, Yuki; Gorospe, Myriam

doi:10.1073/pnas.0809376106

Cited by 195 publications

(195 citation statements)

References 32 publications

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“…The exact role of miR-519c in tumor development remains to be investigated, but it is likely to involve other downstream targets. Besides HIF-1α, a recent report suggests that the miR-519 family represses RNA binding proteins (HuR) and recapitulates cell proliferation in several human carcinoma cells (45). Further, we also noticed several genes, such as IGF, Bcl2, and Myc, which may exert their regulatory activity through miR-519c.…”

Section: Discussionmentioning

confidence: 73%

MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

Ting

Chen²,

Johansson³

et al. 2010

Cancer Research

186

113

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Hypoxia-inducible factor-1α (HIF-1α) is widely considered to be one of the key regulators of tumor angiogenesis. The upstream regulation is complex and involves several growth factors, cytokines, and hypoxia. Herein, we have identified miR-519c as a hypoxia-independent regulator of HIF-1α, acting through direct binding to the HIF-1α 3′ untranslated region and leading to reduced tumor angiogenesis. Overexpression of miR-519c resulted in a significant decrease of HIF-1α protein levels and reduced the tube formation of human umbilical vein endothelial cells; similarly, antagomir inhibition of miR-519c increased the level of HIF-1α protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1α-mediated angiogenesis. Consistent with the overexpression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c-overexpressing cells exhibited dramatically reduced HIF-1α levels, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1α inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was posttranscriptional and may be mediated by suppression of miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and that microenvironmental HGF contributes to regulating miR-519c biogenesis in cancer cells. Cancer Res; 70(7); 2675-85. ©2010 AACR.

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Section: Discussionmentioning

confidence: 73%

MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

Ting

Chen²,

Johansson³

et al. 2010

Cancer Research

186

113

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“…26 In short, 48 hours after transfection, cells were incubated with cycloheximide (100 mg/ml for 15 min; Sigma Aldrich); cytoplasmic lysates (900 ml) were fractionated by centrifugation through 10 to 50% linear sucrose gradients and divided into 12 fractions. From each fraction, RNA was extracted using TriPure Isolation Reagent (Roche Applied Science) and used for RT-qPCR analysis to determine the distribution of VEGFA, HIF1A and ACTB mRNAs on the polysome gradients.…”

Section: Fractionation Of Polyribosomesmentioning

confidence: 99%

Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR

et al. 2015

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These authors equally contributed to the work.Keywords: biotin pulldown, mass spectrometry, post-transcriptional gene regulation, polysome profiling, ribonucleoprotein complex, RNA-binding proteins Vascular endothelial growth factor (VEGF) A is a master regulator of neovascularization and angiogenesis. VEGFA is potently induced by hypoxia and by pathological conditions including diabetic retinopathy and tumorigenesis. Finetuning of VEGFA expression by different stimuli is important for maintaining tissue vascularization and organ homeostasis. Here, we tested the effect of the hypoxia mimetic cobalt chloride (CoCl 2 ) on VEGFA expression in human cervical carcinoma HeLa cells. We found that CoCl 2 increased the levels of VEGFA mRNA and VEGFA protein without affecting VEGFA mRNA stability. Biotin pulldown analysis to capture the RNA-binding proteins (RBPs) bound to VEGFA mRNA followed by mass spectrometry analysis revealed that the RBP HuR [human antigen R, a member of the embryonic lethal abnormal vision (ELAV) family of proteins], interacts with VEGFA mRNA. VEGFA mRNA-tagging experiments showed that exposure to CoCl 2 increases the interaction of HuR with VEGFA mRNA and promoted the colocalization of HuR and the distal part of the VEGFA 3 0 -untranslated region (UTR) in the cytoplasm. We propose that under hypoxia-like conditions, HuR enhances VEGFA mRNA translation.

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“…Notably, HuR has been suggested to participate in malignant transformation process by controlling cancerrelevant genes related with angiogenesis, differentiation, cell cycle, apoptosis, inflammatory response and cell signaling [15,[18][19][20][21]. Moreover, HuR appears to exert a critical role in tumor formation, growth and metastasis by binding to mRNA encoding proteins and by affecting their expression via mRNA stabilization and/or altered translation [15,20,21]. Enhanced HuR expression and cytoplasmic localization have been associated with malignant phenotype and poor patients' prognosis in several human malignancies [18,22].…”

Section: Introductionmentioning

confidence: 99%

Elevated Hu-Antigen Receptor (HuR) Expression is Associated with Tumor Aggressiveness and Poor Prognosis but not with COX-2 Expression in Invasive Breast Carcinoma Patients

Giaginis

Sampani

Kotta-Loizou

et al. 2017

Pathol. Oncol. Res.

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Hu-antigen R (HuR), a RNA-binding protein, is considered to play a crucial role in tumor development and progression by stabilizing or regulating a group of cellular mRNAs of cancer-related genes, such as cyclooxygenase-2 (COX-2). The present study aimed to evaluate the clinical significance of HuR and COX-2 expression in invasive breast carcinoma. HuR and COX-2 protein expression was assessed immunohistochemically on paraffin-embedded breast cancer tissue sections obtained from 121 patients and was statistically analyzed with clinicopathological parameters, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2), as well as with tumor cells' proliferative capacity and overall and disease-free patients' survival. High HuR expression was positively associated with larger tumor size and advanced disease stage (p = 0.0234 and p = 0.0361, respectively), being more frequently observed in ER negative cases (p = 0.0208). High COX-2 expression was negatively associated with histological (p < 0.0001) and nuclear (p = 0.0033) grade and tumor cells' proliferative rate (p = 0.0015), being more frequently observed in luminal-A compared to other molecular subtypes (p = 0.0221). High HuR expression was associated with poor overall and disease-free patients' survival at both univariate (log-rank test, p = 0.0092 and p = 0.0004, respectively) and multivariate (Cox-regression analysis, p = 0.0223 and p = 0.0004, respectively) level. On the other hand, high COX-2 expression was associated with favorable overall and disease-free patients' survival merely at univariate level (log-rank test, p = 0.0389 and p = 0.0154, respectively). HuR expression was not associated with COX-2 expression (Spearman R = 0.1489, p = 0.1032). The present data support evidence that HuR is associated with tumor aggressiveness and poor prognosis in breast carcinoma, reinforcing its potential as promising therapeutic target in this type of neoplasia.

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miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels

Cited by 195 publications

References 32 publications

MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR

Elevated Hu-Antigen Receptor (HuR) Expression is Associated with Tumor Aggressiveness and Poor Prognosis but not with COX-2 Expression in Invasive Breast Carcinoma Patients

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miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels

Cited by 195 publications

References 32 publications

MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

Induction of VEGFA mRNA translation by CoCl2 mediated by HuR

Elevated Hu-Antigen Receptor (HuR) Expression is Associated with Tumor Aggressiveness and Poor Prognosis but not with COX-2 Expression in Invasive Breast Carcinoma Patients

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Induction of VEGFA mRNA translation by CoCl₂ mediated by HuR