Hypoxia‐inducible factors in stem cells and cancer

Mazumdar, Jolly; Dondeti, Vijay R.; Simon, M. Celeste

doi:10.1111/j.1582-4934.2009.00963.x

Cited by 111 publications

(87 citation statements)

References 103 publications

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“…30 This finding is of particular importance, as both normal and tumor stem cells are in vivo harbored in an oxygen poor environment. 37 Previous data reported that RA reduces breast CSC population, while inducing differentiation. 17 Our data show that, among the NRs agonists tested, the RXR agonist IIF is the most active molecule in inhibiting the pro-inflammatory NF-kB/IL6 pathway and in inducing the expression of differentiation markers (KRT18 and ERa) in breast CSCs.…”

Section: Discussionmentioning

confidence: 99%

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

et al. 2012

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Recent literature highlights the importance of pro-inflammatory cytokines in the biology of breast cancer stem cells (CSCs), unraveling differences with respect to their normal counterparts. Expansion of mammospheres (MS) is a valuable tool for the in vitro study of normal and cancer mammary gland stem cells. Here, we expanded MSs from human breast cancer and normal mammary gland tissues, as well from tumorigenic (MCF7) and non-tumorigenic (MCF10) breast cell lines. We observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-c (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells. This phenomenon is paralleled by the hampering of pro-inflammatory Nuclear Factor-jB (NF-jB)/Interleukin-6 (IL6) axis that is hyperactive in breast cancer-derived MS. The hindrance of such pathway associates with the downregulation of MS regulatory genes (SLUG, Notch3, Jagged1) and with the upregulation of the differentiation markers estrogen receptor-a and keratin18. At variance, the PPARa agonist Wy14643 promotes MS formation, upregulating NF-jB/IL6 axis and MS regulatory genes. These data reveal that nuclear receptors agonists (6-OH-11-O-hydroxyphenanthrene, RA, PGZ) reduce the inflammation dependent survival of breast CSCs and that PPARa agonist Wy14643 exerts opposite effects on this phenotype.

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Section: Discussionmentioning

confidence: 99%

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

et al. 2012

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“…HIF-2 ␣, but not HIF-1␣, is a direct upstream regulator of Oct-4 and binds to specific HREs within the promoter of murine Oct-4. 51,56 HIF-1␣ can also directly interact with ␤-catenin and with Notch1. 56 A first clue of the link between Notch and hypoxia derives from studies demonstrating that the Notch target gene Hes1 was up-regulated by hypoxia in neuroblastoma cell lines.…”

Section: Hypoxia and Hif-1␣mentioning

confidence: 99%

“…51,56 HIF-1␣ can also directly interact with ␤-catenin and with Notch1. 56 A first clue of the link between Notch and hypoxia derives from studies demonstrating that the Notch target gene Hes1 was up-regulated by hypoxia in neuroblastoma cell lines. 57 56 Some of these genes contain both HRE-and CSL-binding sites, suggesting that hypoxia and Notch may have additive effects on transcription.…”

Section: Hypoxia and Hif-1␣mentioning

confidence: 99%

Role of Cripto-1 in Stem Cell Maintenance and Malignant Progression

Bianco

Rangel

Castro

et al. 2010

The American Journal of Pathology

112

160

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Cripto-1 is critical for early embryonic development and, together with its ligand Nodal, has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Like other embryonic genes, Cripto-1 performs important roles in the formation and progression of several types of human tumors, stimulating cell proliferation, migration, epithelial to mesenchymal transition, and tumor angiogenesis. Several studies have demonstrated that cell fate regulation during embryonic development and cell transformation during oncogenesis share common signaling pathways, suggesting that uncontrolled activation of embryonic signaling pathways might drive cell transformation and tumor progression in adult tissues. Here we review our current understanding of how Cripto-1 controls stem cell biology and how it integrates with other major embryonic signaling pathways. Because many cancers are thought to derive from a subpopulation of cancer stem-like cells, which may re-express embryonic genes, Cripto-1 signaling may drive tumor growth through the generation or expansion of tumor initiating cells bearing stem-like characteristics. Therefore, the Cripto-1/Nodal signaling may represent an attractive target for treatment in cancer, leading to the elimination of undifferentiated stem-like tumor initiating cells.

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“…This stress can occur during embryonic development, where crowding and rapid cell division causes a shortage of blood and oxygen supply (Keith and Simon 2007;Mazumdar et al 2009). Hypoxia can also be brought on by impaired blood flow due to heart attack or stroke (Semenza 2014a;Ferdinand and Roffe 2016).…”

Section: Introductionmentioning

confidence: 99%

N⁶-methyladenosine is required for the hypoxic stabilization of specific mRNAs

Fry

Law

Ilkayeva

et al. 2017

RNA

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Post-transcriptional regulation of mRNA during oxygen deprivation, or hypoxia, can affect the survivability of cells. Hypoxia has been shown to increase stability of a subset of ischemia-related mRNAs, including VEGF. RNA binding proteins and miRNAs have been identified as important for post-transcriptional regulation of individual mRNAs, but corresponding mechanisms that regulate global stability are not well understood. Recently, mRNA modification by N 6 -methyladenosine (m 6 A) has been shown to be involved in post-transcriptional regulation processes including mRNA stability and promotion of translation, but the role of m 6 A in the hypoxia response is unknown. In this study, we investigate the effect of hypoxia on RNA modifications including m 6 A. Our results show hypoxia increases m 6 A content of poly(A) + messenger RNA (mRNA), but not in total or ribosomal RNA in HEK293T cells. Using m 6 A mRNA immunoprecipitation, we identify specific hypoxia-modified mRNAs, including glucose transporter 1 (Glut1) and c-Myc, which show increased m 6 A levels under hypoxic conditions. Many of these mRNAs also exhibit increased stability, which was blocked by knockdown of m 6 A-specific methyltransferases METTL3/14. However, the increase in mRNA stability did not correlate with a change in translational efficiency or the steady-state amount of their proteins. Knockdown of METTL3/14 did reveal that m 6 A is involved in recovery of translational efficiency after hypoxic stress. Therefore, our results suggest that an increase in m 6 A mRNA during hypoxic exposure leads to post-transcriptional stabilization of specific mRNAs and contributes to the recovery of translational efficiency after hypoxic stress.

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Hypoxia‐inducible factors in stem cells and cancer

Cited by 111 publications

References 103 publications

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

Role of Cripto-1 in Stem Cell Maintenance and Malignant Progression

N⁶-methyladenosine is required for the hypoxic stabilization of specific mRNAs

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Hypoxia‐inducible factors in stem cells and cancer

Cited by 111 publications

References 103 publications

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

Nuclear receptors agonists exert opposing effects on the inflammation dependent survival of breast cancer stem cells

Role of Cripto-1 in Stem Cell Maintenance and Malignant Progression

N6-methyladenosine is required for the hypoxic stabilization of specific mRNAs

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N⁶-methyladenosine is required for the hypoxic stabilization of specific mRNAs