miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1

Hwang‐Verslues, Wendy W.; Chang, Po Hsiang; Wei, Pei‐Chi; Yang, Chengyuan; Huang, Chun-Kai; Kuo, Wen‐Hung; Shew, Jin‐Yuh; Chang, King‐Jen; Lee, Ey-Hp; Lee, W.-H.

doi:10.1038/onc.2010.618

Cited by 178 publications

(124 citation statements)

References 44 publications

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“…Even though MDA-MB-231 cells have undetectable E-cadherin levels, 17 translation repression could be a conserved mode of regulation that can still be observed in these cells like nuclear SNAIL accumulation 52 and miRNA-mediated repression. 53 We highlight that the mTORC1-independent process of eIF4E2-dependent hypoxic translation contributes to cancer cell migration, invasion and spheroid formation.…”

Section: Discussionmentioning

confidence: 88%

Hypoxia activates cadherin-22 synthesis via eIF4E2 to drive cancer cell migration, invasion and adhesion

et al. 2017

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Hypoxia is a driver of cell movement in processes such as development and tumor progression. The cellular response to hypoxia involves a transcriptional program mediated by hypoxiainducible factors, but translational control has emerged as a significant contributor. In this study, we demonstrate that a cell-cell adhesion molecule, cadherin-22, is upregulated in hypoxia via mTORC1-independent translational control by the initiation factor eIF4E2. We identify new functions of cadherin-22 as a hypoxia-specific cell-surface molecule involved in cancer cell migration, invasion and adhesion. Silencing eIF4E2 or cadherin-22 significantly impaired MDA-MB-231 breast carcinoma and U87MG glioblastoma cell migration and invasion only in hypoxia, while reintroduction of the respective exogenous gene restored the normal phenotype. Cadherin-22 was evenly distributed throughout spheroids and required for their formation and support of a hypoxic core. Conversely, E-cadherin translation was repressed by hypoxia and only expressed in the oxygenated cells of U87MG spheroids. Furthermore, immunofluorescence on paraffinembedded human tissue from 40 glioma and 40 invasive ductal breast carcinoma patient specimens revealed that cadherin-22 expression colocalized with areas of hypoxia and significantly correlated with tumor grade and progression-free survival or stage and tumor size, respectively. This study broadens our understanding of tumor progression and metastasis by highlighting cadherin-22 as a potential new target of cancer therapy to disable hypoxic cancer cell motility and adhesion.

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Section: Discussionmentioning

confidence: 88%

Hypoxia activates cadherin-22 synthesis via eIF4E2 to drive cancer cell migration, invasion and adhesion

et al. 2017

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“…3A). REDD1 mRNA is subject to miRNA dependent regulation [18,19]. miRNA processing depends on the RNAse III-type endonuclease Dicer [25].…”

Section: Il-6 Reduces Redd1 Mrna Inductionmentioning

confidence: 99%

“…REDD1-mRNA and protein-turnover are heavily regulated by several miRNAs [18,19] and by ubiquitin-dependent proteasomal degradation [20] or caspase-mediated cleavage [21], respectively.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Jessica

Bongartz

Klepsch

et al. 2016

Cellular Signalling

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Abstract:Interleukin 6 is a pleiotropic cytokine and a strong activator of Mammalian Target of Rapamycin (mTOR). In contrast, mTOR activity is negatively regulated by Regulated in Development and DNA Damage Responses 1 (REDD1). Expression of REDD1 is induced by cellular stressors such as glucocorticoids and DNA damaging agents. We show that the expression of basal as well as stress-induced REDD1 is reduced by IL-6. The reduction of REDD1 expression by IL-6 is independent of proteasomal or caspase-mediated degradation of REDD1 protein. Instead, induction of REDD1 mRNA is reduced by IL-6. The regulation of REDD1 expression by interleukin 6 (IL-6) is independent of Phosphatidylinositide-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signalling but depends on the expression and activation of Signal Transducer and Activator of Transcription 3 (STAT3). Furthermore, the reduction of basal REDD1 expression by IL-6 correlates with IL-6-induced activation of mTOR signalling. Inhibition of STAT3 activation blocks IL-6-induced mTOR activation. In summary, we present a novel STAT3-dependent mechanism of both IL-6-induced activation of mTOR and IL-6-dependent reversion of stress-induced inhibition of mTOR activity.

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“…The integration site locus contains a complex set of imprinted genes that are uniquely dysregulated after reprogramming to pluripotency (11), and two noncoding RNAs (Rian and Mirg) that contain multiple snoRNAs and microRNAs (12). These small RNAs could regulate a large number of target genes, and the human homologs of some of these microRNAs have been proposed to both stimulate and inhibit tumorigenesis in other types of malignancies (13)(14)(15)(16). Two recent studies found that a subset of human HCCs have elevated expression of this microRNA cluster (17,18).…”

mentioning

confidence: 99%

Induction of hepatocellular carcinoma by in vivo gene targeting

Wang¹,

Xu²,

Toffanin

et al. 2012

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

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The distinct phenotypic and prognostic subclasses of human hepatocellular carcinoma (HCC) are difficult to reproduce in animal experiments. Here we have used in vivo gene targeting to insert an enhancer-promoter element at an imprinted chromosome 12 locus in mice, thereby converting ∼1 in 20,000 normal hepatocytes into a focus of HCC with a single genetic modification. A 300-kb chromosomal domain containing multiple mRNAs, snoRNAs, and microRNAs was activated surrounding the integration site. An identical domain was activated at the syntenic locus in a specific molecular subclass of spontaneous human HCCs with a similar histological phenotype, which was associated with partial loss of DNA methylation. These findings demonstrate the accuracy of in vivo gene targeting in modeling human cancer and suggest future applications in studying various tumors in diverse animal species. In addition, similar insertion events produced by randomly integrating vectors could be a concern for liver-directed human gene therapy.

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miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1

Cited by 178 publications

References 44 publications

Hypoxia activates cadherin-22 synthesis via eIF4E2 to drive cancer cell migration, invasion and adhesion

Hypoxia activates cadherin-22 synthesis via eIF4E2 to drive cancer cell migration, invasion and adhesion

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Induction of hepatocellular carcinoma by in vivo gene targeting

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