Role of Ras Signaling in the Induction of Snail by Transforming Growth Factor-β

Horiguchi, Kotaro; Shirakihara, Takuya; Nakano, Ayako; Imamura, Takeshi; Miyazono, Kohei; Saitoh, Masao

doi:10.1074/jbc.m804777200

Cited by 202 publications

(186 citation statements)

References 34 publications

Supporting

Mentioning

173

Contrasting

Order By: Relevance

“…Overexpression of TGF-b ligands and their receptors as well as activating mutations of K-Ras occurs at a very high frequency in PDAC and interactions of these two major pathways have been shown to be crucial in pancreatic carcinogenesis (Lemoine et al, 1992;Friess et al, 1993). In addition, the Ras/ERK cascade has been shown to be activated by members of the TGF-b family contributing to TGF-b-mediated effects, such as EMT (Ellenrieder et al, 2001;Horiguchi et al, 2009). The TGF-b signal transducers Smad2 and Smad3 have also been shown to be phosphorylated by ERK (de Caestecker et al, 1998;Kretzschmar et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Though TGF-b is a tumor suppressor in the early stages of PDAC, it contributes to tumor progression by promoting EMT and invasion in the late cancer stages (Ellenrieder et al, 2001;Hamada et al, 2007). Constitutively active Ras signaling-as a consequence of Kras mutations that are present in 70-90% of PDAChas been shown to be indispensable for TGF-b-mediated induction of EMT (Longnecker and Terhune, 1998;Ellenrieder et al, 2001;Roberts and Wakefield, 2003;Horiguchi et al, 2009). These data suggest that TGF-b cooperates with Ras/ERK signaling in advanced stages of PDAC promoting invasion and metastasis through EMT.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

et al. 2010

View full text Add to dashboard Cite

Epithelial-to-mesenchymal transdifferentiation (EMT) mediated by transforming growth factor-b (TGF-b) signaling leads to aggressive cancer progression. In this study, we identified zinc-a2-glycoprotein (AZGP1, ZAG) as a tumor suppressor in pancreatic ductal adenocarcinoma whose expression is lost due to histone deacetylation. In vitro, ZAG silencing strikingly increased invasiveness of pancreatic cancer cells accompanied by the induction of a mesenchymal phenotype. Expression analysis of a set of EMT markers showed an increase in the expression of mesenchymal markers (vimentin (VIM) and integrin-a5) and a concomitant reduction in the expression of epithelial markers (cadherin 1 (CDH1), desmoplakin and keratin-19). Blockade of endogenous TGF-b signaling inhibited these morphological changes and the downregulation of CDH1, as elicited by ZAG silencing. In a ZAG-negative cell line, human recombinant ZAG (rZAG) specifically inhibited exogenous TGF-b-mediated tumor cell invasion and VIM expression. Furthermore, rZAG blocked TGF-b-mediated ERK2 phosphorylation. PCR array analysis revealed that ZAG-induced epithelial transdifferentiation was accompanied by a series of concerted cellular events including a shift in the energy metabolism and prosurvival signals. Thus, epigenetically regulated ZAG is a novel tumor suppressor essential for maintaining an epithelial phenotype.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Indeed, Ras hyperactivation can increase cell motility by regulating TGF-β signaling, destabilizing E-cadherin/β-catenin complexes, and affecting cytoskeletal dynamics. 9,46 Recent studies suggest an additional mechanism by which DAB2IP inactivation can favor metastasis: in prostate cancer cells loss of DAB2IP correlated with accumulation and activation of Hypoxia-inducible factor 1 (HIF-1α), a key inducer of EMT and cell motility. 47 Similarly, increased HIF-1α and VEGF were observed upon DAB2IP KO in human endothelial cells.…”

Section: Dab2ip Inactivation Fosters Tumor Progressionmentioning

confidence: 99%

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

2016

View full text Add to dashboard Cite

One of the most defining features of cancer is aberrant cell communication; therefore, a molecular understanding of the intricate network established among tumor cells and their microenvironment could significantly improve comprehension and clinical management of cancer. The tumor suppressor DAB2IP (Disabled homolog 2 interacting protein), also known as AIP1 (ASK1 interacting protein), has an important role in this context, as it modulates signal transduction by multiple inflammatory cytokines and growth factors. DAB2IP is a Ras-GAP, and negatively controls Ras-dependent mitogenic signals. In addition, acting as a signaling adaptor, DAB2IP modulates other key oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptors. Therefore, DAB2IP inactivation can provide a selective advantage to tumors initiated by a variety of driver mutations. In line with this role, DAB2IP expression is frequently impaired by methylation in cancer. Interestingly, recent studies reveal that tumor cells can employ other sophisticated mechanisms to disable DAB2IP at the post-transcriptional level. We review the mechanisms and consequences of DAB2IP inactivation in cancer, with the purpose to support and improve research aimed to counteract such mechanisms. We suggest that DAB2IP reactivation in cancer cells could be a strategy to coordinately dampen multiple oncogenic pathways, potentially limiting progression of a wide spectrum of tumors.

show abstract

“…6,7 Snail is a key regulator of EMT, and represses the gene expression of E-cad-herin, a hallmark of the epithelial phenotype. 8 Other commonly used molecular markers for EMT include reduced expression of cytokeratin (CK), increased expression of vimentin, S100A4 and N-cadherin, and nuclear localization of ␤-catenin.…”

mentioning

confidence: 99%

Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β1/Snail Activation Aggravates Invasive Growth of Cholangiocarcinoma

Sato

Harada

Itatsu

et al. 2010

The American Journal of Pathology

View full text Add to dashboard Cite

Epithelial-mesenchymal transition is an important mechanism behind initiation of cancer invasion and metastasis. This study was performed to clarify the involvement of epithelial-mesenchymal transition in the progression of cholangiocarcinoma. Cholangiocarcinoma cell lines, CCKS-1 and TFK-1, were treated with transforming growth factor-␤1 (TGF-␤1), and the phenotypic changes and invasive activity were examined. Immunohistochemical analysis was performed using tissue sections of cholangiocarcinoma. In vitro, TGF-␤1 induced mesenchymal features in CCKS-1 and TFK-1 characterized by the reduction of E-cadherin and cytokeratin 19 expression and the induction of mesenchymal markers , such as vimentin and S100A4. TGF-␤1 also induced the nuclear expression of Snail , and the invasive activity was significantly increased in both cell lines. Studies using a mouse xenograft model showed that TGF-␤1 worsened the peritoneal dissemination of CCKS-1. All these changes by TGF-␤1 were inhibited by the simultaneous administration of soluble TGF-␤ type II receptor. In vivo, six (16%) of 37 cholangiocarcinoma cases showed marked immunoreactivity of Snail in their nuclei. In these six cases, the immuno-expression of cytokeratin 19 was significantly reduced , and the expression of vimentin was significantly increased. The Snail expression significantly correlated with the lymph node metastasis and a poor survival rate of the patients. These results suggest that epithelial-mesenchymal transition induced by TGF-␤1/Snail activation is closely associated with the aggressive growth of cholangiocarcinoma, resulting in a poor

show abstract

Role of Ras Signaling in the Induction of Snail by Transforming Growth Factor-β

Cited by 202 publications

References 34 publications

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β1/Snail Activation Aggravates Invasive Growth of Cholangiocarcinoma

Contact Info

Product

Resources

About