RUNX1: A MicroRNA Hub in Normal and  Malignant Hematopoiesis

Rossetti, Stefano; Sacchi, Nicoletta

doi:10.3390/ijms14011566

Cited by 41 publications

(36 citation statements)

References 157 publications

(197 reference statements)

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“…The importance of miRNA regulation of Runx1 and associated normal and abnormal physiological processes is well documented in hematopoiesis and leukemia, respectively [34]. However, the significance of these regulatory interactions is unknown in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, miRNAs that target the Runx transcription factor family are known to be involved in cancer. Runx1 is required of normal hematopoiesis, while numerous Runx1 translocations cause multiple hematopoietic malignancies, serving as the nexus of a complex regulatory miRNA circuitry [34]. Runx2, a bone essential transcription factor, promotes metastasis to bone because it is abnormally expressed in cancer cells due to missing miRNAs that target Runx2 [21, 35]; and Runx3, essential for nerve and gut development, is suppressed by several miRNAs that are elevated in cancer cells which results in promoting gastric cancer [36–38].…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells

et al. 2016

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The Runx1 transcription factor, known for its essential role normal hematopoiesis, was reported in limited studies to be mutated or associated with human breast tumor tissues. Runx 1 increases concomitant with disease progression in the MMTV-PyMT transgenic mouse model of breast cancer. Compelling questions relate to mechanisms that regulate Runx1 expression in breast cancer. Here, we tested the hypothesis that dysregulation of Runx1-targeting microRNAs (miRNAs) allows for pathologic increase of Runx1 during breast cancer progression. Microarray profiling of the MMTV-PyMT model revealed significant down-regulation of numerous miRNAs predicted to target Runx1. One of these, miR-378, was inversely correlated with Runx1 expression during breast cancer progression in mouse, and in human breast cancer cell lines MCF7 and triple negative MDA-MB-231 that represent early and late stage disease, respectively. MiR-378 is nearly absent in MDA-MB-231 cells. Luciferase reporter assays revealed that miR-378 binds the Runx1 3′UTR and inhibits Runx1 expression. Functionally, we demonstrated that ectopic expression of miR-378 in MDA-MB-231 cells inhibited Runx1 and suppressed migration and invasion; while inhibition of miR-378 in MCF7 cells increased Runx1 levels and cell migration. Depletion of Runx1 in late stage breast cancer cells resulted in increased expression of both the miR-378 host gene PPARGC1B and pre-miR-378, suggesting a feedback loop. Taken together, our study identifies a novel and clinically relevant mechanism for regulation of Runx1 in breast cancer that is mediated by a PPARGC1B-miR-378-Runx1 regulatory pathway. Our results highlight the translational potential of miRNA replacement therapy for inhibiting Runx1 in breast cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells

et al. 2016

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“…In skin squamous cell carcinoma, RUNX1 is overexpressed and its action is thought to be mediated by the repression of p21 and activation of STAT3. RUNX1 is associated with tumorigenesis in colon cancer, whereas in breast cancer, its role as a tumor suppressor or oncogene remains unclear [21,22]. RUNX1 is highly overexpressed in invasive endometrial carcinoma, and the colocalization, upregulation and codistribution of RUNX1 with matrix metalloproteases in both endometrioid endometrial and ovarian endometrioid carcinoma (OEC) suggests that it plays a role in the progression and invasion of OEC [23,24].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-302b Suppresses Human Epithelial Ovarian Cancer Cell Growth by Targeting RUNX1

Yin

Yang

et al. 2014

Cell Physiol Biochem

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Background: The microRNA (miR)-302 family functions as a tumor suppressor in human cancer. However, its role in epithelial ovarian carcinoma (EOC) remains unknown. Here, we investigated the role of miR-302b and its target gene RUNX1 in EOC. Methods: The expression levels of miR-302b and RUNX1 were assessed by quantitative real-time PCR and western blotting. The effects of ectopic expression of miR-302b were evaluated by the MTT assay, colony forming assay and flow cytometry. RUNX1 was identified as a target of miR-302b and their interaction was confirmed by luciferase activity assays, RUNX1 silencing and overexpression of a RUNX1 mutant construct lacking the 3′UTR. The effect of miR-302b on the suppression of tumor growth was investigated in vivo in a xenograft mouse model. Results: MiR-302b levels were markedly decreased in EOC specimens. Ectopic expression of miR-302b in EOC cells inhibited cell proliferation and colony formation, induced G0/G1 arrest, and promoted apoptosis. RUNX1 was identified as a direct target of miR-302b, and knockdown of RUNX1 inhibited cell growth in a manner similar to miR-302b overexpression, whereas introduction of a 3′UTR mutant of RUNX1 reversed the suppressive effect of miR-302b. Furthermore, miR-302b overexpression led to the inactivation of the STAT3 signaling pathway in EOC cells and inhibited tumor growth in a xenograft mouse model. Conclusions: MiR-302b functions as a tumor suppressor in EOC by targeting RUNX1 and modulating the activity of the STAT3 signaling pathway.

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“…116 Translation of Runx1 is also subject to regulation by microRNAs. 117,118 Several alternatively spliced transcripts have been described in mouse (Figure 3) and human, 119 including the full-length P1-and P2-derived Runx1c and Runx1b. One of these transcripts, RUNX1a, lacks the transactivation domain while retaining the DNA-binding domain and has been proposed to act as a dominant negative.…”

Section: Structure Of Mammalian Runx Genes and Alternatively Spliced mentioning

confidence: 99%

Runx transcription factors in the development and function of the definitive hematopoietic system

Bruijn

Dzierzak

2017

Blood

153

103

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The Runx family of transcription factors (Runx1, Runx2, and Runx3) are highly conserved and encode proteins involved in a variety of cell lineages, including blood and blood-related cell lineages, during developmental and adult stages of life. They perform activation and repressive functions in the regulation of gene expression. The requirement for Runx1 in the normal hematopoietic development and its dysregulation through chromosomal translocations and loss-of-function mutations as found in acute myeloid leukemias highlight the importance of this transcription factor in the healthy blood system. Whereas another review will focus on the role of Runx factors in leukemias, this review will provide an overview of the normal regulation and function of Runx factors in hematopoiesis and focus particularly on the biological effects of Runx1 in the generation of hematopoietic stem cells. We will present the current knowledge of the structure and regulatory features directing lineage-specific expression of Runx genes, the models of embryonic and adult hematopoietic development that provide information on their function, and some of the mechanisms by which they affect hematopoietic function.

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RUNX1: A MicroRNA Hub in Normal and Malignant Hematopoiesis

Cited by 41 publications

References 157 publications

MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells

MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells

MicroRNA-302b Suppresses Human Epithelial Ovarian Cancer Cell Growth by Targeting RUNX1

Runx transcription factors in the development and function of the definitive hematopoietic system

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