The transcription factor Net regulates the angiogenic switch

Zheng, Hong; Wasylyk, Christine; Ayadi, A.; Abecassis, Joseph; Schalken, Jack A.; Rogatsch, Hermann; Wernert, Nicolas; Maira, Sauveur‐Michel; Multon, Marie-Christine; Wasylyk, Bohdan

doi:10.1101/gad.272503

Cited by 64 publications

(86 citation statements)

References 73 publications

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“…It can, in particular, induce the VEGF. We have previously shown that Net is an indirect activator of VEGF, and that inhibition of Net in an in vivo model of tumorigenicity leads to inhibition of tumour growth, impaired angiogenesis and persistence of large hypoxic regions (Zheng et al, 2003). Our results suggest that the Net-HIF-1a pathway, discovered in the current study, could be involved in these processes.…”

Section: Discussionsupporting

confidence: 69%

“…Net is involved in various physiological processes, including angiogenesis. Net regulates cell migration through repression of PAI-1 , and is required for tumour growth in xenographs (Zheng et al, 2003). Mice that express mutant Net lacking its DNA binding domain exhibit respiratory distress (Ayadi et al, 2001), and delayed wound healing due to impaired angiogenesis (Zheng et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Net regulates cell migration through repression of PAI-1 , and is required for tumour growth in xenographs (Zheng et al, 2003). Mice that express mutant Net lacking its DNA binding domain exhibit respiratory distress (Ayadi et al, 2001), and delayed wound healing due to impaired angiogenesis (Zheng et al, 2003). We have recently shown that Net is downregulated in hypoxia and is required for the regulation of several genes in response to hypoxia (Gross et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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The ternary complex factor Net/Elk-3 participates in the transcriptional response to hypoxia and regulates HIF-1α

2007

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The ternary complex factor Net/Elk3 is downregulated in hypoxia and participates in the induction by hypoxia of several genes, including c-fos, vascular endothelial growth factor and egr-1. However, the global role of Net in hypoxia remains to be elucidated. We have identified, in a large-scale analysis of RNA expression using microarrays, more than 370 genes that are regulated by Net in hypoxia. In order to gain insights into the role of Net in hypoxia, we have analysed in parallel the genes regulated by HIF-1a, the classical factor involved in the response to hypoxia. We identified about 190 genes that are regulated by HIF-1a in hypoxia. Surprisingly, when we compare the genes induced by hypoxia that require either Net or HIF1a, the majority are the same (75%), suggesting that the functions of both factors are closely linked. Interestingly, in hypoxia, Net regulates the expression of several genes known to control HIF-1a stability, including PHD2, PHD3 and Siah2, suggesting that Net regulates the stability of HIF-1a. We found that inhibition of Net by RNAi leads to decreased HIF-1a expression at the protein level in hypoxia. These results indicate that Net participates in the transcriptional response to hypoxia by regulation of HIF-1a protein stability.

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Section: Discussionsupporting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The ternary complex factor Net/Elk-3 participates in the transcriptional response to hypoxia and regulates HIF-1α

2007

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“…ELK3 is activated by mitogen-activated protein kinase (MAPK)-associated pathways, such as the Ras/extracellular signal-regulated kinase (ERK) and p38 pathways, and it plays an important role in various physiological processes, including cell migration, invasion, wound healing, angiogenesis and tumorigenesis, via the regulation of c-fos, early growth response protein 1 (egr-1), and plasminogen activator inhibitor-1 (PAI-1) (19)(20)(21)(22)(23). Mutations in ELK3 disrupt vasculogenesis, angiogenesis and wound healing in mice during development and in adulthood (24,25). In addition, our previous study demonstrated that ELK3 contributes to epithelial-mesenchymal transition (EMT) of mouse hepatocytes by regulating egr-1 (26).…”

Section: Elk3 Promotes the Migration And Invasion Of Liver Cancer Stementioning

confidence: 99%

ELK3 promotes the migration and invasion of liver cancer stem cells by targeting HIF-1α

et al. 2016

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Abstract. Hepatocellular carcinoma (HCC) is the fifth most common solid cancer and the third most common cause of cancer-related mortality. HCC develops via a multistep process associated with genetic aberrations that facilitate HCC invasion and migration and promote metastasis. A growing body of evidence indicates that cancer stem cells (CSCs) are responsible for tumorigenesis, cancer cell invasion and metastasis. Despite the extremely small proportion of cancer cells represented by this subpopulation of HCC cells, CSCs play a key role in cancer metastasis and poor prognosis. ELK3 (Net/SAP-2/Erp) is a transcription factor that is activated by the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. It plays several important roles in various physiological processes, including cell migration, invasion, wound healing, angiogenesis and tumorigenesis. In the present study, we investigated the role of ELK3 in cancer cell invasion and metastasis in CD133 + /CD44 + liver cancer stem cells (LCSCs). We isolated LCSCs expressing CD133 and CD44 from Huh7 HCC cells and evaluated their metastatic potential using invasion and migration assays. We found that CD133 + /CD44 + cells had increased metastatic potential compared with non-CD133 + /CD44 + cells. We also demonstrated that ELK3 expression was upregulated in CD133 + /CD44 + cells and that this aberration enhanced cell migration and invasion. In addition, we identified the molecular mechanism by which ELK3 promotes cancer cell migration and invasion. We found that silencing of ELK3 expression in CD133 + /CD44 + LCSCs attenuated their metastatic potential by modulating the expression of heat shock-induced factor-1α (HIF-1α). Collectively, the results of the present study demonstrated that ELK3 overexpression promoted metastasis in CD133 + /CD44 + cells by regulating HIF-1α expression and that silencing of ELK3 expression attenuated the metastatic potential of CD133 + /CD44 + LCSCs. In conclusion, modulation of ELK3 expression may represent a novel therapeutic strategy for preventing HCC metastasis and invasion.

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“…Recently, members of the TCF family of SRF cofactors have been characterized by knock-out studies. Elk-1 deficient mice display normal immune responses and mildly impaired neuronal gene inactivation (44) and Net mutants show defects in cell migration (45), vasculature development (46), and impaired angiogenesis during wound healing (47). The strongest phenotype with regard to immune functions is observed in SAP-1-null mice where thymocyte development is severely impaired and a decrease in the amount of CD4 ϩ and CD8 ϩ single positive (SP) cells is seen resulting from defective thymocyte positive selection (48).…”

mentioning

confidence: 99%