Identification of Hypoxia-Inducible Factor-1α as a Novel Target for <i>miR-17-92</i> MicroRNA Cluster

Taguchi, Ayumu; Yanagisawa, Kiyoshi; Tanaka, Masaharu; Cao, Ke; Matsuyama, Yasushi; Goto, Hidemi; Takahashi, Takashi

doi:10.1158/0008-5472.can-07-6460

Cited by 280 publications

(201 citation statements)

References 19 publications

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“…Dicer-dependent generation of miR-185, was found to target HIF-2α transcripts. In addition, miR-17-92 cluster regulates HIF-1α via c-myc (20). A recent study demonstrated an intricate relationship between miR-20a, HIF-1α, and c-Myc (21).…”

Section: Discussionmentioning

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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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: 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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“…Moreover, miR-17-92 is included in the c-myc-mediated repression of hypoxia-inducible factor1a (HIF-1a). 8 HIF-1a plays a role in cell proliferation during hypoxia, and its upregulation in CLL bone marrow biopsies was linked with microvessel proliferation. Interestingly, other hypoxia-associated miRNA family miR-23 has a higher expression in the unmutated IgV H samples (Figures 2c and d).…”

Section: Letters To the Editormentioning

confidence: 97%

miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities

et al. 2009

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“…117 Second, they also target the VEGF transcription factor, HIF-1a. 123,124 Third, these miRNAs are reported to regulate VEGF-mediated endothelial cell migration via the MEK/MAPK pathway. 125 Cancer cells exploit miRNA regulation of angiogenesis and promote tumor growth by downregulating VEGF-targeting miRNAs (miR-17, -20, -199a and -125b), 118,121 tipping the scale towards conditions favoring angiogenesis.…”

Section: Microrna Regulation Of Angiogenesismentioning

confidence: 99%

MicroRNAs, immune cells and pregnancy

et al. 2014

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MicroRNAs (miRNAs) are a recently discovered class of non-coding RNAs that are expressed in many cell types, where they regulate the expression of complementary RNAs, thus modulating the stability and translation of mRNAs. miRNAs are predicted to regulate the expression of ,50% of all protein coding genes in mammals. Therefore, they participate in virtually all cellular processes investigated so far. Altered miRNAs expressions are associated with both physiological (pregnancy) and pathological processes (cancer). As the dynamic maternal-fetal interface plays a critical role in the maintenance of successful pregnancy, it is not surprising that the miRNAs that are unique to reproductive tissues are abundantly expressed. Research in this field has demonstrated the presence and dysregulation of a distinct set of pregnancy-associated miRNAs; however, most studies have centered on localizing various miRNAs in reproductive microdomains associated with normal or complicated pregnancies. Although several independent miRNA regulatory mechanisms associated with endometrial receptivity, immune cells, angiogenesis and placental development have been studied, miRNA-mediated regulation of pregnancy remains poorly understood. This review provides a summary of the current data on miRNA regulation as well as functional profiles of miRNAs that are found in the uterus, in immune cells associated with maternal tolerance to the fetus, and those involved in angiogenesis and placental development.

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Identification of Hypoxia-Inducible Factor-1α as a Novel Target for miR-17-92 MicroRNA Cluster

Cited by 280 publications

References 19 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

miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities

MicroRNAs, immune cells and pregnancy

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