Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis

Chen, Zhe; Lai, Tsung‐Ching; Jan, Yi-Hua; Lin, Feng‐Mao; Wang, Wei-Chi; Xiao, Han; Wang, Yunting; Sun, Wei; Cui, Xiaopei; Li, Ying-Shiuan; Fang, Tzan; Zhao, Hongwei; Padmanabhan, Chellappan; Sun, Ruobai; Wang, Danny Ling; Jin, Hailing; Chau, Gar‐Yang; Huang, Hsien-Da; Hsiao, Michael; Shyy, John Y.‐J.

doi:10.1172/jci65344

Cited by 156 publications

(160 citation statements)

References 49 publications

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“…Hypoxia down-regulates Dicer and thereby alters microRNA biogenesis. Furthermore, hypoxia-responsive miRNAs regulate argonaute1 (AGO1) and affect miR targeting (18). Our studies suggest that individual micro-RNA could be differentially regulated by transcriptional suppression.…”

Section: Discussionmentioning

confidence: 83%

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Joshi¹,

Subramanian²,

Schnettler³

et al. 2014

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

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Hypoxia-driven changes in the tumor microenvironment facilitate cancer metastasis. In the present study, we investigated the regulatory cross talk between endocytic pathway, hypoxia, and tumor metastasis. Dynamin 2 (DNM2), a GTPase, is a critical mediator of endocytosis. Hypoxia decreased the levels of DNM2. DNM2 promoter has multiple hypoxia-inducible factor (HIF)-binding sites and genetic deletion of them relieved hypoxia-induced transcriptional suppression. Interestingly, DNM2 reciprocally regulated HIF. Inhibition of DNM2 GTPase activity and dominantnegative mutant of DNM2 showed a functional role for DNM2 in regulating HIF. Furthermore, the opposite strand of DNM2 gene encodes miR-199a, which is similarly reduced in cancer cells under hypoxia. miR-199a targets the 3′-UTR of HIF-1α and HIF-2α. Decreased miR-199a expression in hypoxia increased HIF levels. Exogenous expression of miR-199a decreased HIF, cell migration, and metastasis of ovarian cancer cells. miR-199a-mediated changes in HIF levels affected expression of the matrix-remodeling enzyme, lysyloxidase (LOX). LOX levels negatively correlated with progression-free survival in ovarian cancer patients. These results demonstrate a regulatory relationship between DNM2, miR199a, and HIF, with implications in cancer metastasis.microRNA | iron regulation E pithelial ovarian cancer (EOC) is the leading cause of death among the gynecological malignancies (1). Ascites development and peritoneal metastasis are unique features of ovarian cancer progression. Gas analyses of ovarian cancer ascites show about 2.5% dissolved oxygen content, whereas the blood oxygen content ranges between 15% and 23% (2). Hypoxic areas are common in tumor microenvironment as increased metabolic demands of rapidly proliferating cells outpace oxygen availability. Sustained exposure to hypoxia spurs cells to reorganize cellular processes, and energy-consuming functions, such as endocytosis, are suppressed (3, 4). Hypoxia-inducible factor-1α and hypoxia-inducible factor-2α (HIF-1α/HIF-2α) are principal coordinators of these responses. HIF-1α/HIF-2α are stabilized in hypoxia and associate with hypoxia-inducible factor-1β (HIF-1β) to form heterodimeric transcription factors and induce the expression of target genes (5, 6). HIF-1-mediated expression of lysyloxidase (LOX) cross-links collagens and induces cell migration (7). Epithelial ovarian cancer cells (EOCCs) that have adapted to hypoxia by activating HIF-1 disseminate from primary ovarian tumors and exfoliate into the peritoneal cavity. HIF-1 significantly enhances gene signatures associated with tissue remodeling, the morbidity and mortality associated with EOC (8, 9).Regulation of HIF-1 is a key step in the hypoxic response with profound implications for EOC metastasis. Under normoxia, HIF-1α is hydroxylated within its oxygen-dependent degradation domain (ODDD) by prolylhydroxylases (PHDs). This reaction is an oxygen-, iron-, 2-oxoglutarate and ascorbate-dependent process. Hydroxylated HIF-1α is recognized and bound by a complex that...

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Section: Discussionmentioning

confidence: 83%

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Joshi¹,

Subramanian²,

Schnettler³

et al. 2014

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

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“…Our previous study has also shown that let-7g could directly bind to THBS1 3 0 UTR and knock down its expression [10]. A recent study showed that several let-7 family members have hypoxia regulated/responsive elements in their promoters, and HIF-1a-induced let-7 could directly suppress AGO1 [11]. AGO1 is involved in miRNA-mediated silencing complex (miR-ISC) that causes gene silencing.…”

Section: Discussionmentioning

confidence: 99%

“…AGO1 is involved in miRNA-mediated silencing complex (miR-ISC) that causes gene silencing. VEGF-A is translationally suppressed by AGO1-miRISC under normoxia and let-7 can increase VEGF-A by repressing AGO1-miRISC leading to VEGF-A RNA release [11]. Accordingly, let-7g has multiple routes to increase VEGF-A.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA let‐7g possesses a therapeutic potential for peripheral artery disease

Hsu

Hsi

Wang

et al. 2016

J Cellular Molecular Medi

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Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis and conveys a significant health burden globally. Critical limb ischaemia encompasses the most severe consequence of PAD. Our previous studies indicate that microRNA let-7g prevents atherosclerosis and improves endothelial functions. This study aimed to investigate whether and how let-7g therapy may improve blood flow to ischaemic limbs. The present study shows that let-7g has multiple pro-angiogenic effects on mouse ischaemic limb model and could be a potential therapeutic agent for PAD. Mice receiving intramuscular injection of let-7g had more neovascularization, better local perfusion and increased recruitment of endothelial progenitor cells after hindlimb ischaemia. The therapeutic effects of let-

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“…The important role of miRNA has been shown re cently in the regulation of cellular response to hypoxia. In particular, Let7 and miR103/107 favor the VEGF induction by targeting argonaute 1 protein [23] .…”

Section: Molecular Insights Into the Angiogenic Processmentioning

confidence: 99%

Mechanisms of adaptation of the hepatic vasculature to the deteriorating conditions of blood circulation in liver cirrhosis

Garbuzenko

Arefyev

Belov

2016

WJH

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PubMed, EMBASE, Orphanet, MIDLINE, Google Scholar and Cochrane Library were searched for articles published between 1983 and 2015. Relevant articles were selected by using the following terms: "Liver cirrhosis", "Endothelial dysfunction", "Sinusoidal remodeling", "Intrahepatic angiogenesis" and "Pathogenesis of portal hypertension". Then the reference lists of identified articles were searched for other relevant publications as well. Besides gross hepatic structural disorders related to diffuse fibrosis and formation of regenerative nodules, the complex morphofunctional rearrangement of the hepatic microvascular bed and intrahepatic angiogenesis also play important roles in hemodynamic disturbances in liver cirrhosis. It is characterized by endothelial dysfunction and impaired paracrine interaction between activated stellate hepatocytes and sinusoidal endotheliocytes, sinusoidal remodeling and capillarization, as well as development of the collateral microcirculation. In spite of the fact that complex morphofunctional rearrangement of the hepatic microvascular bed and intrahepatic angiogenesis in liver cirrhosis are the compensatory-adaptive reaction to the deteriorating conditions of blood circulation, they contribute to progression of disease and development of serious complications, in particular, related to portal hypertension.

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Hypoxia-responsive miRNAs target argonaute 1 to promote angiogenesis

Cited by 156 publications

References 49 publications

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

Dynamin 2 along with microRNA-199a reciprocally regulate hypoxia-inducible factors and ovarian cancer metastasis

MicroRNA let‐7g possesses a therapeutic potential for peripheral artery disease

Mechanisms of adaptation of the hepatic vasculature to the deteriorating conditions of blood circulation in liver cirrhosis

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