ERK2 but Not ERK1 Induces Epithelial-to-Mesenchymal Transformation via DEF Motif-Dependent Signaling Events

Shin, Sang Yong; Dimitri, Christopher A.; Yoon, Sang-Oh; Dowdle, William E.; Blenis, John

doi:10.1016/j.molcel.2010.02.020

Cited by 272 publications

(330 citation statements)

References 44 publications

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“…Several reports have connected Fra-1/AP-1 in human breast cancer to increased expression of the EMT-TFs Zeb1 and Zeb2 and to a lesser extent Slug. [12][13][14][15]17 We investigated whether Fra-1/AP-1 and the EMT-TFs also correlated in mouse mammary EMT. Expression of Fra-1 in EpH4 cells induced EMT and increased proliferation, migration and invasiveness.…”

Section: Discussionmentioning

confidence: 99%

“…Our findings are consistent with reports that Fra-1 affects the proliferation and motility of human breast cancer cell lines 17,42 and that Fra-1 is a critical EMT effector downstream of Ras signalling. 13,14 Ras and TGFβ cooperate to induce and stabilize a mesenchymal switch in EpH4 cells. 21,22,40 Unlike human breast cancer cells where upstream signalling kinases activation is required, 14,16 ectopic Fra-1 expression was sufficient for EMT and tumorigenesis in EpH4 cells.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 Ras and TGFβ cooperate to induce and stabilize a mesenchymal switch in EpH4 cells. 21,22,40 Unlike human breast cancer cells where upstream signalling kinases activation is required, 14,16 ectopic Fra-1 expression was sufficient for EMT and tumorigenesis in EpH4 cells. Moreover, Fra-1 increased TGFβ expression and production, similarly to c-Fos and unlike oncogenic Ras, 43 thus TGFβ treatment was not necessary for EMT in EpFra1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…We demonstrated that Fra-1 binds to two regions in the murine tgfb1 promoter containing several AP-1-binding elements. As autocrine TGFβ production has also been observed in human breast cancer cells, where extracellular signal-regulated kinase 2 (ERK2)-induced EMT depends on Fra-1 14 and as Fra-1 binds the human TGFB2 gene in colorectal cancer cells, 44 it is tempting to speculate that Fra-1/AP-1 modulates the transcription of TGFB genes in the context of EMT. However, inhibition of TGFβ signalling in EpFra1 cells only partially restored epithelial markers expression, similarly to the situation during Fos-or ERK2-induced EMT.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Strikingly, suppression of Fra-1 restores epithelial characteristics, including E-cadherin expression, and abrogates the invasive potential of human breast cancer cell lines. 12,13 Furthermore, Fra-1 has been implicated in human breast cancer EMT through increased expression of the Snai2/Slug, Zinc finger E-box-binding homeobox 1 (Zeb1) and Zeb2 EMT-TFs, [13][14][15][16][17] although the mechanisms how Fra-1 modulates EMT-TFs expression are not fully understood.…”

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Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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Epithelial-to-mesenchymal transition (EMT) is essential for embryonic morphogenesis and wound healing and critical for tumour cell invasion and dissemination. The AP-1 transcription factor Fra-1 has been implicated in tumorigenesis and in tumour-associated EMT in human breast cancer. We observed a significant inverse correlation between Fra-1 mRNA expression and distant-metastasis-free survival in a large cohort of breast cancer patients derived from multiple array data sets. This unique correlation among Fos genes prompted us to assess the evolutionary conservation between Fra-1 functions in EMT of human and mouse cells. Ectopic expression of Fra-1 in fully polarized, non-tumourigenic, mouse mammary epithelial EpH4 cells induced a mesenchymal phenotype, characterized by a loss of epithelial and gain of mesenchymal markers. Proliferation, motility and invasiveness were also increased in the resulting EpFra1 cells, and the cells were tumourigenic and efficiently colonized the lung upon transplantation. Molecular analyses revealed increased expression of Tgfβ1 and the EMT-inducing transcription factors Zeb1, Zeb2 and Slug. Mechanistically, Fra-1 binds to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1. Furthermore, increased activity of a zeb2 promoter reporter was detected in EpFra1 cells and shown to depend on AP-1-binding sites. Inhibiting TGFβ signalling in EpFra1 cells moderately increased the expression of epithelial markers, whereas silencing of zeb1 or zeb2 restored the epithelial phenotype and decreased migration in vitro and tumorigenesis in vivo. Thus Fra-1 induces changes in the expression of genes encoding EMT-related transcription factors leading to the acquisition of mesenchymal, invasive and tumorigenic capacities by epithelial cells. This study defines a novel function of Fra-1/AP-1 in modulating tgfb1, zeb1 and zeb2 expression through direct binding to genomic regulatory regions, which establishes a basis for future in vivo genetic manipulations and preclinical studies using mouse models. Epithelial-to-mesenchymal transition (EMT) is a complex biological programme that occurs in physiological processes during embryonic development and wound healing as well as in pathological conditions, such as organ fibrosis and carcinogenesis. During EMT, cells lose epithelial features and acquire mesenchymal characteristics. The acquisition of a mesenchymal state by malignant cancer cells is associated with decreased cell-cell adhesion, and increased migratory and invasive properties, which are crucial for metastasis. [1][2][3][4][5] The adherens junction (AJ) protein E-cadherin, encoded by cdh1, is a central determinant of the epithelial state and its downregulation is the hallmark of EMT. A number of molecular pathways converging on E-cadherin have been implicated in EMT. Transcription factors (TF) of the Snail, Zeb and Twist families, initially identified as regulators of epithelialmesenchymal plasticity during morphogenesis were shown to orchestrate EMT by...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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Intraportal transplantation of human bone marrow mesenchymal stem cells in pigs with fulminant hepatic failure

Li¹,

Li²

2013

Hepatology

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We read with interest the article by Li et al. 1 The authors demonstrated that intraportal transplantation of human bone marrow mesenchymal stem cells (hBMSCs) in pigs with fulminant hepatic failure (D-galactosamine model), significantly improved their longterm survival (87%) compared to both peripheral vein transplantation and sham groups (0%). One of the most interesting findings is that 30% of the recipient liver was repopulated by transplanted hBMSC-derived hepatocytes in surviving animals 2 to 10 weeks post-transplantation. We also learn from this study that hBMSCderived hepatocytes were well differentiated and expressed hepatocyte-specific markers for albumin, CK8, G6PD, and HNF-1a. In addition, high levels of human-derived albumin were identified in the pig sera; 2.02 6 0.35 g/L and 3.92 6 0.5 g/L at week 2 and week 10, respectively. We wonder, and as reported by others, that mature hepatocyte should also express human leukocyte antigen-1 triggering host immune response leading to xenograft rejection. [2][3][4] Do the authors have experimental data to show that hBMSCderived hepatocytes did not trigger an immune response in these animals?The authors mention that both treated and control groups did not receive any medications or infusions. Usually, in fulminant hepatic failure patients, complications like hypoglycemia, dyselectrolytemia, and renal dysfunction are very common. Data on blood glucose, serum sodium, and renal function would be of interest in all 3 groups to understand the severity of liver failure, particularly if we are contemplating translation of this work to humans.

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MEP1A contributes to tumor progression and predicts poor clinical outcome in human hepatocellular carcinoma

Ouyang

Luo

et al. 2016

Hepatology

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Although many staging classifications have been proposed for hepatocellular carcinoma (HCC), determining a patient's prognosis in clinical practice is a challenge due to the molecular diversity of HCC. We investigated the relationship between MEP1A, a candidate oncogene, and clinical outcomes of HCC patients; furthermore, we explored the role of MEP1A in HCC. In this report, it was demonstrated by quantitative real-time polymerase chain reaction that MEP1A messenger RNA levels were significantly elevated in HCC tumor tissues compared with matched adjacent nonneoplastic tissues and nonmalignant liver disease tissues. Immunohistochemical analyses of tissue samples from two independent groups of 394 HCC patients showed that positive expression of MEP1A in tumor cells was an independent and significant risk factor affecting survival after curative resection in both cohort 1 (hazard ratio 5 2.05, 95% confidence interval 1.427-2.946; P < 0.001) and cohort 2 (hazard ratio 5 1.89, 95% confidence interval 1.260-2.833; P 5 0.002). Analysis of Barcelona Clinic Liver Cancer stage 0-A subgroup further showed that patients with positive MEP1A expression in tumor cells had poorer surgical prognoses than those with negative MEP1A expression in tumor cells (cohort 1 P 5 0.001, cohort 2 P < 0.001). Both in vitro and in vivo assays showed that MEP1A promoted HCC cell proliferation, migration, and invasion. Further analyses found that MEP1A played an important role in regulating cytoskeletal events and induced epithelial-mesenchymal transition in HCC cells. Conclusion: MEP1A is a novel prognostic predictor in HCC and plays an important role in the development and progression of HCC.

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ERK2 but Not ERK1 Induces Epithelial-to-Mesenchymal Transformation via DEF Motif-Dependent Signaling Events

Cited by 272 publications

References 44 publications

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

Intraportal transplantation of human bone marrow mesenchymal stem cells in pigs with fulminant hepatic failure

MEP1A contributes to tumor progression and predicts poor clinical outcome in human hepatocellular carcinoma

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