Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-α isoforms and promotes angiogenesis

Ghosh, Goutam; Subramanian, Indira V.; Adhikari, Neeta; Zhang, Xiaoxiao; Joshi, Hemant; Basi, David L.; Chandrashekhar, Y.; Hall, Jennifer L.; Roy, Sabita; Zeng, Yan; Ramakrishnan, Sundaram

doi:10.1172/jci42980

Cited by 385 publications

(301 citation statements)

References 75 publications

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“…Immunoblotting was carried out as per previously published methods (28). ChIP was carried out as per manufacturer's instructions using ExactaChIP Human/Mouse HIF-1α from R&D Systems in normoxic and hypoxic conditions.…”

Section: Methodsmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 99%

“…Scratch wound assays, lentiviral vector construction, transduction, and luciferase assays were carried out as per previously published methods (28).…”

Section: Methodsmentioning

confidence: 99%

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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“…MiR-92-1 targets the von Hippel-Lindau (VHL) tumor suppressor [93], an E3 ubiquitin ligase which marks HIF1α for degradation in the presence of oxygen. Under hypoxia, miR-424 upregulation in endothelial cells stabilizes HIF1α through the targeting of cullin 2, a scaffolding protein critical to the assembly of ubiquitin ligase system [94]. Glycerol-3-phosphate dehydrogenase 1-like (GPD1L), an inhibitor of HIF-1α stability is a direct target of miR-210.…”

Section: Hif1 and Myc Transcription Factorsmentioning

confidence: 99%

miRNAs link metabolic reprogramming to oncogenesis

Hatziapostolou¹,

Polytarchou²,

Iliopoulos

2013

Trends in Endocrinology & Metabolism

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“…HIF-1a can be targeted by the miR-17-92 cluster, miR-424 and miR-20b. [11][12][13] A specific group of miRNAs have been reported to be induced in response to hypoxia, at least partially via an HIF-1-dependent mechanism. 14 However, much less is known about possible effects of HIF-1 on the expression of miRNAs, and the role that this regulation may have in AML cells.…”

mentioning

confidence: 99%

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

et al. 2012

Cell Death Differ

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Hypoxia-inducible factor 1 (HIF-1) is a crucial transcription factor for the cellular adaptive response to hypoxia, which contributes to multiple events in cancer biology. MicroRNAs (miRNAs) are involved in almost all cellular activities such as differentiation, proliferation, and apoptosis. In this work, we use miRNA microarrays to profile miRNA expression in acute myeloid leukemia (AML) cells with inducible HIF-1a expression, and identify 19 differentially expressed miRNAs. Our study shows that HIF-1a represses the expression of miR-17 and miR-20a by downregulating c-Myc expression. These two miRNAs alleviate hypoxia and HIF-1a-induced differentiation of AML cells. More intriguingly, miR-17 and miR-20a directly inhibit the p21 and STAT3 (signal transducer and activator of transcription 3) expression, both of which can reverse miR-17/miR-20a-mediated abrogation of HIF-1a-induced differentiation. Moreover, we show in vivo that miR-20a contributes to HIF-1a-induced differentiation of leukemic cells. Taken together, our results suggest that HIF-1a regulates the miRNA network to interfere with AML cell differentiation, representing a novel molecular mechanism for HIF-1-mediated anti-leukemic action. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcriptional factor that consists of the oxygen-sensitive alpha subunit (HIF-1a) and the constitutively expressed beta subunit (HIF-1b), is a master regulator for the cellular adaptive response to oxygen concentration. 1 Under normoxic conditions, proline residues 402 and 564 of the HIF-1a protein are hydroxylated by specific prolyl hydroxylases (PHDs) that utilize O 2 and a-ketoglutarate as co-factors. The hydroxylated HIF-1a protein is subject to ubiquitination by the E3 ubiquitin ligase von Hippel-Lindau (VHL), which leads to its degradation. In contrast, hypoxic conditions cause the accumulation of HIF-1a protein by inhibiting its hydroxylation, and subsequent ubiquitination and degradation. 2 The stabilized HIF-1a protein translocates into the nucleus, where it forms a heterodimer with HIF-1b and modulates the expression of hundreds of genes through binding to hypoxia-responsive elements (HREs; 5 0 -RCGTG-3 0 ) on their promoters. These HIF-1-targeted genes help the cell adapt to hypoxia by influencing processes such as erythropoiesis, angiogenesis, cell metabolism, growth, apoptosis, and differentiation.Intriguingly, HIF-1a has been shown to contribute to the pathogenesis and progression of multiple kinds of diseases, including cancer. 1,3 Although a hypoxic microenvironment is regarded as a hallmark of solid tumors, and hypoxia-stabilized HIF-1a protein contributes to tumor growth, angiogenesis, and metastasis, 4 several groups, including our own, have reported that HIF-1a protein can trigger acute myeloid leukemia (AML) cells to undergo differentiation through a transcription-independent mechanism, inhibiting the progression of AML. [5][6][7][8][9] MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs of around 22 nucleotides in length that posttra...

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Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-α isoforms and promotes angiogenesis

Cited by 385 publications

References 75 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

miRNAs link metabolic reprogramming to oncogenesis

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

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