Up-Regulation of α5-Integrin by E-Cadherin Loss in Hypoxia and Its Key Role in the Migration of Extravillous Trophoblast Cells during Early Implantation

Arimoto-Ishida, Emi; Sakata, Masahiro; Sawada, Kenjiro; Nakayama, Masahiro; Nishimoto, Fumihito; Mabuchi, Seiji; Takeda, Takashi; Yamamoto, Takatsugu; Isobe, Aki; Okamoto, Yoko; Lengyel, Ernst; Suehara, Noriyuki; Morishige, Ken‐ichirou; Kimura, Tadashi

doi:10.1210/en.2008-1662

Cited by 46 publications

(37 citation statements)

References 37 publications

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“…They suggested that during early placentation, low-oxygen tension up-regulates SNAIL in EVTs, which in turn down-regulates E-cadherin expression and subsequently increases adhesion and invasion. 53 This preliminary evidence of a role for SNAIL in placental cells is consistent with a potentially important role in early placental development and EMT, which warrants further investigation. SLUG is another member of the SNAIL family of transcriptional repressors.…”

Section: Transcriptional Regulation Of Emtsupporting

confidence: 63%

“…The inverse relationship between SNAIL and E-cadherin observed in epithelial and cancer cells also exists in a number of trophoblast cell lines. 52,53 Arimoto-Ishida et al, 53 investigated the role of SNAIL in trophoblast invasion and showed that down-regulating SNAIL siRNA resulted in decreased invasiveness of trophoblast-derived cell lines. They suggested that during early placentation, low-oxygen tension up-regulates SNAIL in EVTs, which in turn down-regulates E-cadherin expression and subsequently increases adhesion and invasion.…”

Section: Transcriptional Regulation Of Emtmentioning

confidence: 99%

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Epithelial-mesenchymal transition during extravillous trophoblast differentiation

Davies

Pollheimer

Yong

et al. 2016

Cell Adhesion & Migration

209

146

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A successful pregnancy depends on the intricate and timely interactions of maternal and fetal cells. Placental extravillous cytotrophoblast invasion involves a cellular transition from an epithelial to mesenchymal phenotype. Villous cytotrophoblasts undergo a partial epithelial to mesenchymal transition (EMT) when differentiating into extravillous cytotrophoblasts and gain the capacity to migrate and invade. This review summarizes our current knowledge regarding known regulators of EMT in the human placenta, including the inducers of EMT, upstream transcription factors that control EMT and the downstream effectors, cell adhesion molecules and their differential expression and functions in pregnancy pathologies, preeclampsia (PE) and fetal growth restriction (FGR). The review also describes the research strategies that were used for the identification of the functional role of EMT targets in vitro. A better understanding of molecular pathways driven by placental EMT and further elucidation of signaling pathways underlying the developmental programs may offer novel strategies of targeted therapy for improving feto-placental growth in placental pathologies including PE and FGR.

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Section: Transcriptional Regulation Of Emtsupporting

confidence: 63%

Section: Transcriptional Regulation Of Emtmentioning

confidence: 99%

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

Davies

Pollheimer

Yong

et al. 2016

Cell Adhesion & Migration

209

146

View full text Add to dashboard Cite

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“…Activity of this enhancer is associated with enrichment of H3 Lys (4) dimethylation and H3 acetylation of both the enhancer and promoter. Although hypoxia has been implicated in upregulation of Snail (19)(20)(21), no functional hypoxia-responsive element has been identified in the snail promoter.…”

Section: D a Bmentioning

confidence: 99%

“…GSK-3 is an endogenous inhibitor of Snail transcription (17) and GSK-3b mediated phosphorylation of Snail has been shown to facilitate its proteasomal degradation (18). Low oxygen induces Snail transcription (19)(20)(21)(22) and both the canonical HIF (22,23) and Notch (24,25) pathways have been implicated in hypoxia-induced EMT. However, Snail is yet to be identified as a direct HIF target gene.…”

Section: Introductionmentioning

confidence: 99%

Mouse Snail Is a Target Gene for HIF

Luo

Wang

et al. 2011

Molecular Cancer Research

102

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The transcriptional inhibitor Snail is a critical regulator for epithelial-mesenchymal transition (EMT). Although low oxygen induces Snail transcription, thereby stimulating EMT, a direct role of hypoxia-inducible factor (HIF) in this process remains to be demonstrated. Here we show that hypoxia induces the expression of Snail via HIF. In silico analysis identified a potential hypoxia-response element (HRE) close to the minimal promoter of the human and mouse genome of the snail gene. Gel shift assays demonstrated that a specific hypoxiainducible complex is formed with the putative HRE and that the complex contains HIF proteins. ChIP assays confirmed the interaction of HIF proteins with the putative HRE in vivo. Reporter gene analyses showed that the putative HRE responds to hypoxia in its natural position as well as in front of a heterologous promoter and that the HRE is directly activated by HIF-1a or HIF-2a. HIF knockdown with siRNA at 2% oxygen and overexpression of an oxygen-insensitive HIF (HIF-DODD) mutant at 21% oxygen showed that HIF regulates Snail activation and subsequent cell migration. Our findings identify snail as a HIF target gene and provide novel insights into the regulation of snail and hypoxia-induced EMT. Mol Cancer Res; 9(2); 234-45. Ó2011 AACR.

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“…In mammals, 18 ␣ and 8 ␤ subunits have been characterized, which combine to generate 24 unique integrin heterodimers (26). Multiple integrin subunits are up-regulated under hypoxic conditions in a range of cell types (5,27,28). Among these, integrin ␣3␤1 is an enigmatic member of the integrin family, and the regulation of its function also marks it as distinct from that of other integrins (29).…”

mentioning

confidence: 99%

Hypoxia-induced Changes to Integrin α 3 Glycosylation Facilitate Invasion in Epidermoid Carcinoma Cell Line A431

Ren

Hao

Law

et al. 2014

Molecular & Cellular Proteomics

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Hypoxia is a critical microenvironmental factor that drives cancer progression through angiogenesis and metastasis. Glycoproteins, especially those on the plasma membrane, orchestrate this process; however, questions remain regarding hypoxia-perturbed protein glycosylation in cancer cells. We focused on the effects of hypoxia on the integrin family of glycoproteins, which are central to the cellular processes of attachment and migration and have been linked with cancer in humans. We employed electrostatic repulsion hydrophilic interaction chromatography coupled with iTRAQ labeling and LC-MS/MS to identify and quantify glycoproteins expressed in A431. The results revealed that independent of the protein-level change, N-glycosylation modifications of integrin ␣ 3 (ITGA3) were inhibited by hypoxia, unlike in other integrin subunits. A combination of Western blot, flow cytometry, and cell staining assays showed that hypoxia-induced alterations to the glycosylation of ITGA3 prevented its efficient translocation to the plasma membrane. Mutagenesis studies demonstrated that simultaneous mutation of glycosites 6 and 7 of ITGA3 prevented its accumulation at the K562 cell surface, which blocked integrin ␣ 3 and ␤ 1 heterodimer formation and thus abolished ITGA3's interaction with extracellular ligands. By generating A431 cells stably expressing ITGA3 mutated at glycosites 6 and 7, we showed that lower levels of ITGA3 on the cell surface, as induced by hypoxia, conferred an increased invasive ability to cancer cells in vitro under hypoxic conditions. Taken together, these results revealed that ITGA3 translocation to the plasma membrane suppressed by hypoxia through inhibition of glycosylation facilitated cell invasion in A431. Molecular & Cellular Proteomics 13: 10.1074/mcp.M114.038505, 3126-3137, 2014.As solid tumors grow, those areas distant from the existing blood vessels can become chronically or intermittently deprived of sufficient oxygen. These hypoxic conditions place tremendous pressure on tumor cells and drive the development of increasingly malignant and metastatic phenotypes (1, 2). As metastases are responsible for more than 90% of human cancer-related deaths, much research has aimed to define the underlying molecular mechanisms of the tumor cell response to a hypoxic microenvironment (3-5). However, despite the evident clinical relevance of metastasis, the full complexity of the process remains incompletely understood. An emerging area of interest is the importance of the carbohydrate structures in tumor cells, which have been linked to control of protein folding and stability, cell-cell recognition, adhesion, invasion, and metastatic potentials (6 -11). The post-translational enzymatic addition of glycans (glycosylation) to proteins is a potent modulator of the functions of many receptors involved in cell growth, adhesion, and signal transduction (11)(12)(13)(14) and is commonly seen in both in vitro and in vivo cancer models (15, 16). Furthermore, a growing body of studies has shown a clear correlation betw...

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Up-Regulation of α5-Integrin by E-Cadherin Loss in Hypoxia and Its Key Role in the Migration of Extravillous Trophoblast Cells during Early Implantation

Cited by 46 publications

References 37 publications

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

Mouse Snail Is a Target Gene for HIF

Hypoxia-induced Changes to Integrin α 3 Glycosylation Facilitate Invasion in Epidermoid Carcinoma Cell Line A431

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