The Myc–miR-17∼92 Axis Blunts TGFβ Signaling and Production of Multiple TGFβ-Dependent Antiangiogenic Factors

Dews, Michael; Fox, Jamie L.; Hultine, Stacy; Sundaram, Prema; Wang, Wenge; Liu, Yingqiu Y.; Furth, Emma E.; Enders, Greg H.; El‐Deiry, Wafik S.; Schelter, Janell M.; Cleary, Michele A.; Thomas-Tikhonenko, Andrei

doi:10.1158/0008-5472.can-10-2412

Cited by 252 publications

(220 citation statements)

References 60 publications

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“…12 Mir-17B92 may also inhibit the TGFb pathway and attenuate its antiangiogenic effects. 44 Furthermore, it has been shown that miR-92 may target the von Hippel --Lindau gene product, and increases VEGF expression. 45 The miR-17B92 cluster is known to be upregulated by the E2F family.…”

Section: Discussionmentioning

confidence: 99%

The miRNA-17∼92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation

et al. 2011

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The median survival of patients with mantle cell lymphoma (MCL) ranges from 3 to 5 years with current chemotherapeutic regimens. A common secondary genomic alteration detected in MCL is chromosome 13q31-q32 gain/amplification, which targets a microRNA (miRNA) cluster, miR-17B92. On the basis of gene expression profiling, we found that high level expression of C13orf25, the primary transcript from which these miRNAs are processed, was associated with poorer survival in patients with MCL (P ¼ 0.021). We demonstrated that the protein phosphatase PHLPP2, an important negative regulator of the PI3K/AKT pathway, was a direct target of miR-17B92 miRNAs, in addition to PTEN and BIM. These proteins were down-modulated in MCL cells with overexpression of the miR-17B92 cluster. Overexpression of miR-17B92 activated the PI3K/AKT pathway and inhibited chemotherapy-induced apoptosis in MCL cell lines. Conversely, inhibition of miR-17B92 expression suppressed the PI3K/AKT pathway and inhibited tumor growth in a xenograft MCL mouse model. Targeting the miR-17B92 cluster may therefore provide a novel therapeutic approach for patients with MCL.

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Section: Discussionmentioning

confidence: 99%

The miRNA-17∼92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation

et al. 2011

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“…miRNAs belonging to this cluster, attenuating also the TGF signaling pathway, indirectly shut down clusterin and angiopoietin-like 4 expressions, thereby stimulating angiogenesis and tumor cell growth [106]. Accordingly, blockade of miR-17 is shown to decrease breast cancer cell invasion/migration in vitro and metastasis in vivo [107].…”

Section: Mirnas and Metastasismentioning

confidence: 99%

microRNA: New Players in Metastatic Process

Triulzi¹,

Iorio²,

Tagliabue³

et al. 2013

Oncogene and Cancer - From Bench to Clinic

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“…The region encoding for this cluster, C13orf25, is amplified in multiple types of lymphomas, including diffuse large B-cell lymphoma, follicular lymphoma, and some solid tumors (6). Its wide spectrum of validated targets implies effects on multiple signaling pathways, such as BMP, TGF, and PI3K signaling involved in development and disease (7)(8)(9)(10)(11)(12). It is well known that individual miRNAs of this cluster can cooperate or work independently to efficiently modulate multiple signaling pathways, as has been demonstrated for miR-19, which drives the oncogenic ability of this cluster in the context of a MYC-driven B-cell lymphoma (9).…”

mentioning

confidence: 99%

Endothelial miR-17∼92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling

Landskroner-Eiger

Qiu

Perrotta

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The contribution of endothelial-derived miR-17∼92 to ischemiainduced arteriogenesis has not been investigated in an in vivo model. In the present study, we demonstrate a critical role for the endothelial-derived miR-17∼92 cluster in shaping physiological and ischemiatriggered arteriogenesis. Endothelial-specific deletion of miR-17∼92 results in an increase in collateral density limbs and hearts and in ischemic limbs compared with control mice, and consequently improves blood flow recovery. Individual cluster components positively or negatively regulate endothelial cell (EC) functions in vitro, and, remarkably, ECs lacking the cluster spontaneously form cords in a manner rescued by miR-17a, -18a, and -19a. Using both in vitro and in vivo analyses, we identified FZD4 and LRP6 as targets of miR-19a/b. Both of these targets were up-regulated in 17∼92 KO ECs compared with control ECs, and both were shown to be targeted by miR-19 using luciferase assays. We demonstrate that miR-19a negatively regulates FZD4, its coreceptor LRP6, and WNT signaling, and that antagonism of miR-19a/b in aged mice improves blood flow recovery after ischemia and reduces repression of these targets. Collectively, these data provide insights into miRNA regulation of arterialization and highlight the importance of vascular WNT signaling in maintaining arterial blood flow.endothelium | arteriogenesis | vascular | microRNA

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The Myc–miR-17∼92 Axis Blunts TGFβ Signaling and Production of Multiple TGFβ-Dependent Antiangiogenic Factors

Cited by 252 publications

References 60 publications

The miRNA-17∼92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation

The miRNA-17∼92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation

microRNA: New Players in Metastatic Process

Endothelial miR-17∼92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling

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