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Gordon B Mills - One of the best experts on this subject based on the ideXlab platform.

  • abstract b40 Transcription Factor Snail mediates emt by altering vesicular trafficking protein rab25
    2016
    Co-Authors: Shreya Mitra, Lorenzo Federico, Gordon B Mills
    Abstract:

    Epithelial cells maintain intercellular communication directly by cell-cell, cell-ECM interaction and indirectly by paracrine secretion of extracellular messengers either as free molecules or via exosomes. The vesicular trafficking machinery is an integral part of such communication, paralleling digital cables that transmit the information bytes to the correct hub. During the process of EMT, derailing of the trafficking machinery leads to a systemic breakdown of intra and inter-cellular communication pathways. The purpose of the current study is to elucidate the functional role of Rab25, a key member of the vesicular trafficking machinery in mediating EMT-MET processes during breast cancer progression. Aberrant endocytosis is a new hallmark of cancer. Rab GTPases are the primary regulators of endocytosis. Many members of this large family are implicated in a wide array of cancers including breast cancer. Specifically, Rab25, a GTPase associated with the recycling endosomes, is deregulated in most epithelial cancers. Rab25 appears to function both as a tumor suppressor and an oncogene in a context dependent manner. We found that Rab25 is lost in Claudin Low tumors as well as in representative cell lines such as the MDA MB231. Rab25 is a robust and sufficient marker of breast cancers and cell lines with an increased EMT signature. Additionally, in immortalized human mammary epithelial cell lines (HMLE), induction of EMT by overexpression of Snail1 completely obliterates Rab25 protein. Exogenous re-expression of Rab25 dramatically rescues these cells from Snail driven invasion through Matrigel. However this Snail dependent regulation is unique only to TN and Claudin Low tumors and does not hold true for hormone receptor positive tumors. Further, analysis of RNA Seq data from a MMTV mouse model showed that tumors enriched in EMT markers and by corollary with low CDH and claudins, also lost Rab25 transcripts. Snail mediated Transcriptional repression targets recycling endosomal proteins such as Rab25 to decrease delivery of junction proteins that facilitate cell-cell communication to the appropriate compartment. In parallel, it potentially enhances paracrine regulation by secreted exosomes. Overall, our study shows presence and absence of Rab25 markedly alters cell-cell communication, which is essential for maintenance of epithelial features of cells. Rab25 could be a prognostic marker and a therapeutic target for a subset of patients with increased risk of metastatic disease. Citation Format: Shreya Mitra, Lorenzo Federico, Gordon B. Mills. Transcription Factor Snail mediates EMT by altering vesicular trafficking protein Rab25. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B40.

  • abstract 4040 Transcription Factor Snail mediates emt by altering vesicular trafficking protein rab25
    2015
    Co-Authors: Shreya Mitra, Lorenzo Federico, Tapashree Roysarkar, Sendurai A Mani, Gordon B Mills
    Abstract:

    Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Epithelial cells maintain intercellular communication directly by cell-cell, cell-ECM interaction and indirectly by paracrine secretion of extracellular messengers either as free molecules or via exosomes. The vesicular trafficking machinery is an integral part of such communication, paralleling digital cables that transmit the information bytes to the correct hub. During the process of EMT, derailing of the trafficking machinery leads to a systemic breakdown of intra and inter-cellular communication pathways. The purpose of the current study is to elucidate the functional role of Rab25, a key member of the vesicular trafficking machinery in mediating EMT-MET processes during breast cancer progression. Aberrant endocytosis is a new hallmark of cancer. Rab GTPases are the primary regulators of endocytosis. Many members of this large family are implicated in a wide array of cancers including breast cancer. Specifically, Rab25, a GTPase associated with the recycling endosomes, is deregulated in most epithelial cancers. Rab25 appears to function both as a tumor suppressor and an oncogene in a context dependent manner. We found that Rab25 is lost in Claudin Low tumors as well as in representative cell lines such as the MDA MB231. Rab25 is a robust and sufficient marker of breast cancers and cell lines with an increased EMT signature. Additionally, in immortalized human mammary epithelial cell lines (HMLE), induction of EMT by overexpression of Snail1 completely obliterates Rab25 protein. Exogenous re-expression of Rab25 dramatically rescues these cells from Snail driven invasion through MatrigelTM. However this Snail dependent regulation is unique only to TN and Claudin Low tumors and does not hold true for hormone receptor positive tumors. Further, analysis of RNA Seq data from a MMTV mouse model showed that tumors with low CDH1/Claudins expression and enriched in EMT markers also lost Rab25 transcripts. Snail mediated Transcriptional repression targets recycling endosomal proteins such as Rab25 to decrease delivery of junction proteins that facilitate cell-cell communication to the appropriate compartment. In parallel, it potentially enhances paracrine regulation by secreted exosomes. Overall, our study shows presence and absence of Rab25 markedly alters cell-cell communication, which is essential for maintenance of epithelial features of cells. Rab25 could be a prognostic marker and a therapeutic target for a subset of patients with increased risk of metastatic disease. Note: This abstract was not presented at the meeting. Citation Format: Shreya Mitra, Lorenzo Federico, Tapashree Roysarkar, Sendurai Mani, Gordon B. Mills. Transcription Factor Snail mediates EMT by altering vesicular trafficking protein Rab25. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4040. doi:10.1158/1538-7445.AM2015-4040

Masayuki Ozawa - One of the best experts on this subject based on the ideXlab platform.

  • the Transcription Factor Snail expressed in cutaneous squamous cell carcinoma induces epithelial mesenchymal transition and down regulates cox 2
    2013
    Co-Authors: Mitsuyoshi Shimokawa, Misako Haraguchi, Wakako Kobayashi, Yuko Higashi, Shigeto Matsushita, Kazuhiro Kawai, Takuro Kanekura, Masayuki Ozawa
    Abstract:

    Abstract Cutaneous spindle cell squamous cell carcinoma (SCC) is a rare, but highly malignant variant of SCC. The presence of spindle-shaped cells with a sarcomatous appearance, which are derived from squamous cells, suggests that these cells are produced as a result of epithelial–mesenchymal transition (EMT). EMT is a complex process in which epithelial cells lose their polarity and cell–cell contacts, while also acquiring increased motility and invasiveness. Snail regulates EMT by binding to proximal E-boxes in the promoter region of E-cadherin and repressing its Transcription. When examining the expression of EMT markers and Snail in spindle cell SCCs, we found that cyclooxygenase-2 (COX-2) expression was down-regulated. Since it has been shown that COX-2 is constitutively overexpressed in a variety of malignancies, including colon, gastric, and lung carcinomas, the down-regulation of COX-2 expression was unexpected. The presence of E-box-like sequences in the promoter region of COX-2 prompted us to perform a more detailed analysis. We introduced a Snail expression vector into keratinocyte-derived cell lines (HaKaT, HSC5, and A431 cells), and isolated stable transfectants. We determined that COX-2 expression was down-regulated in cells expressing Snail. Consistent with these observations, reporter assays revealed that COX-2 promoter activity was repressed upon Snail overexpression. Thus Snail down-regulates COX-2 in these cells.

  • The Transcription Factor Snail enhanced the degradation of E-cadherin and desmoglein 2 in oral squamous cell carcinoma cells
    2013
    Co-Authors: Kenichi Kume, Misako Haraguchi, Hiroshi Hijioka, Takayuki Ishida, Akihiko Miyawaki, Norifumi Nakamura, Masayuki Ozawa
    Abstract:

    Epithelial–mesenchymal transition (EMT), a key process in the tumor metastatic cascade, is characterized by the loss of cell–cell junctions and cell polarity as well as the acquisition of migratory and invasive properties. However, the precise molecular events that initiate this complex EMT process are poorly understood. Snail is a regulator of EMT that represses E-cadherin Transcription through its interaction with proximal E-boxes in the promoter region of target genes. To investigate the role of Snail in EMT, we generated stable Snail transfectants using the oral squamous cell carcinoma cell line HSC-4 (Snail/HSC-4). Snail/HSC-4 cells had a spindle-shaped mesenchymal morphology, and enhanced migration and invasiveness relative to control cells. Consistent with these EMT changes, the downregulation of epithelial marker proteins, E-cadherin and desmoglein 2, and the upregulation of mesenchymal marker proteins, vimentin and N-cadherin were detected. Despite these observations, the mRNA levels of E-cadherin and desmoglein 2 did not decrease significantly. Although E-cadherin and desmoglein 2 proteins were stable in parental HSC-4 cells, these proteins were rapidly degraded in Snail/HSC-4 cells. The degradation of E-cadherin, but not desmoglein 2, was inhibited by dynasore, an inhibitor of dynamin-dependent endocytosis. Therefore, in HSC-4 cells Snail regulates levels of these proteins both Transcriptionally and post-translationally.

  • the Transcription Factor Snail downregulates the tight junction components independently of e cadherin downregulation
    2004
    Co-Authors: Tadashi Ohkubo, Masayuki Ozawa
    Abstract:

    Snail, a Transcriptional repressor of E-cadherin expression, is involved in epithelial-mesenchymal transitions during development. We demonstrate that Snail activity is not restricted to E-cadherin downregulation. Expression of tight junction proteins, including claudin-1, occludin and ZO-1, was downregulated in MDCK cells exogenously expressing Snail protein. Although occludin mRNA levels were downregulated by Snail expression, the Transcription of claudin-1 and ZO-1 were unaffected. Reporter assays using the claudin-1 promoter region revealed that promoter activity was not affected by Snail overexpression. Decreased synthesis of claudin-1 protein was observed, however, suggesting that Snail may act in translation initiation. Snail expression also altered the splicing pattern of p120. The levels of mRNA encoding the epithelial variant decreased, while the fibroblastic mRNA form increased. Although ectopic E-cadherin expression resulted in a downregulation of Snail-induced fibronectin expression, fibroblastic morphology was affected only minimally; the expression of tight junctional proteins remained at low levels. These results indicate that Snail is involved in both the direct Transcriptional repression of genes, such as E-cadherin and occludin, and post-Transcriptional events, including downregulation of claudin-1. These data support the idea that Snail is a Transcription Factor possessing pleiotropic activities.

Sheila E Francis - One of the best experts on this subject based on the ideXlab platform.

  • author correction shear stress induces endothelial to mesenchymal transition via the Transcription Factor Snail
    2020
    Co-Authors: Marwa Mahmoud, Jovana Serbanoviccanic, Shuang Feng, Celine Souilhol, Rouyu Xing, Sarah Hsiao, Akiko Mammoto, Jing Chen, Markus Ariaans, Sheila E Francis
    Abstract:

    textabstractAn amendment to this paper has been published and can be accessed via a link at the top of the paper.

  • shear stress induces endothelial to mesenchymal transition via the Transcription Factor Snail
    2017
    Co-Authors: Marwa Mahmoud, Jovana Serbanoviccanic, Shuang Feng, Celine Souilhol, Rouyu Xing, Sarah Hsiao, Akiko Mammoto, Jing Chen, Markus Ariaans, Sheila E Francis
    Abstract:

    Blood flow influences atherosclerosis by generating wall shear stress, which alters endothelial cell (EC) physiology. Low shear stress induces dedifferentiation of EC through a process termed endothelial-to-mesenchymal transition (EndMT). The mechanisms underlying shear stress-regulation of EndMT are uncertain. Here we investigated the role of the Transcription Factor Snail in low shear stress-induced EndMT. Studies of cultured EC exposed to flow revealed that low shear stress induced Snail expression. Using gene silencing it was demonstrated that Snail positively regulated the expression of EndMT markers (Slug, N-cadherin, α-SMA) in EC exposed to low shear stress. Gene silencing also revealed that Snail enhanced the permeability of endothelial monolayers to macromolecules by promoting EC proliferation and migration. En face staining of the murine aorta or carotid arteries modified with flow-altering cuffs demonstrated that Snail was expressed preferentially at low shear stress sites that are predisposed to atherosclerosis. Snail was also expressed in EC overlying atherosclerotic plaques in coronary arteries from patients with ischemic heart disease implying a role in human arterial disease. We conclude that Snail is an essential driver of EndMT under low shear stress conditions and may promote early atherogenesis by enhancing vascular permeability.

Volker Fendrich - One of the best experts on this subject based on the ideXlab platform.

  • expression of the Transcription Factor Snail and its target gene twist are associated with malignancy in pheochromocytomas
    2009
    Co-Authors: Jens Waldmann, Emily P Slater, P Langer, Malte Buchholz, Annette Ramaswamy, Martin K Walz, K W Schmid, Georg Feldmann, Detlef K Bartsch, Volker Fendrich
    Abstract:

    Background One of the best known functions of the zinc-finger Transcription Factor Snail is to induce epithelial-mesenchymal transition (EMT). Twist, a target genes of Snail, is known to promote the development of distant metastases in mice. Increasing evidence suggests that EMT plays a pivotal role in tumor progression and metastatic spread.

  • expression of the zinc finger Transcription Factor Snail in adrenocortical carcinoma is associated with decreased survival
    2008
    Co-Authors: Jens Waldmann, Emily P Slater, P Langer, Malte Buchholz, Annette Ramaswamy, Georg Feldmann, Volker Fendrich, W Saeger, M Rothmund
    Abstract:

    In this study, we evaluate whether Snail is expressed in adrenocortical cancer (ACC) and if its expression is related to patient outcome. One of the best known functions of the zinc-finger Transcription Factor Snail is to induce epithelial-to-mesenchymal transition (EMT). Increasing evidence suggests that EMT plays a pivotal role in tumour progression and metastatic spread. Snail and E-cadherin expression were assessed by immunohistochemistry in 26 resected ACCs and real-time quantitative RT–PCR expression analysis was performed. Data were correlated with clinical outcome and in particular with overall patient survival. Seventeen of 26 (65%) ACC tumour samples expressed Snail when assessed by immunohistochemistry. Snail expression was neither detected in normal adrenocortical tissue, nor in benign adrenocortical adenomas. Expression levels were confirmed on the mRNA level by Real-Time–PCR. Survival rates were significantly decreased in Snail-positive tumours compared to Snail-negative tumours: 10 out of 16 vs one out of eight patients succumbed to disease after a median follow up of 14.5 and 28.5 months, respectively (P=0.03). Patients with Snail-expressing ACCs presented in advanced disease (11 out of 12 vs 6 out of 14, P=0.01) and tend to develop distant metastases more frequently than patients with negative staining (7 out of 11 vs two out of eight, P=0.19). In conclusion, we describe for the first time that Snail is expressed in a large subset of ACCs. Furthermore, Snail expression is associated with decreased survival, advanced disease and higher risk of developing distant metastases.

  • Snail and sonic hedgehog activation in neuroendocrine tumors of the ileum
    2007
    Co-Authors: Volker Fendrich, Jens Waldmann, Malte Buchholz, Annette Ramaswamy, Farzad Esni, Michael Mullendore, Anirban Maitra, Georg Feldmann
    Abstract:

    The Transcription Factor Snail represses E-cadherin and induces epithelial–mesenchymal transition, a process also exploited by invasive cancer cells. Aberrant Hedgehog (Hh) signaling was recently observed in a variety of epithelial cancers and it has been shown that the Hh target geneGli1 induces expression of Snail. In this study, we examined whether Snail and Sonic Hedgehog (SHH) are expressed in neuroendocrine tumors (NETs) of the ileum. Using immunohistochemistry, we found expression of Snail in 22 out of 37 (59%) of evaluated NET samples, but not in adjacent normal tissues. Snail expression was mostly restricted to the invasive front of the tumors. Six of seven liver metastases analyzed were positive for Snail. Intratumoral expression of SHH was detected in 27 out of 37 (73%) tumors. As opposed to Snail, cells expressing SHH were found to be distributed more randomly throughout the tumors. Out of 30 primary NETs, 16 (53%) showed both Snail and SHH expression. Furthermore, we found downregulation of E-cadherin in Snail-expressing cells by immunofluorescence. Real-time RT-PCR revealed conservation of the Hh target genes Gli1, Gli2, and Ptch in the pancreatic carcinoid cell line BON-1, which were downregulated upon Hh inhibition with cyclopamine. Moreover, Hh inhibition attenuated in vitro cell growth in a dose-dependent manner. In conclusion, we describe for the first time that Snail and SHH are overexpressed in a large subset of NETs of the ileum. Aberrant activation of these pathways might be involved in invasion and metastatic spread in NETs.

Shreya Mitra - One of the best experts on this subject based on the ideXlab platform.

  • abstract b40 Transcription Factor Snail mediates emt by altering vesicular trafficking protein rab25
    2016
    Co-Authors: Shreya Mitra, Lorenzo Federico, Gordon B Mills
    Abstract:

    Epithelial cells maintain intercellular communication directly by cell-cell, cell-ECM interaction and indirectly by paracrine secretion of extracellular messengers either as free molecules or via exosomes. The vesicular trafficking machinery is an integral part of such communication, paralleling digital cables that transmit the information bytes to the correct hub. During the process of EMT, derailing of the trafficking machinery leads to a systemic breakdown of intra and inter-cellular communication pathways. The purpose of the current study is to elucidate the functional role of Rab25, a key member of the vesicular trafficking machinery in mediating EMT-MET processes during breast cancer progression. Aberrant endocytosis is a new hallmark of cancer. Rab GTPases are the primary regulators of endocytosis. Many members of this large family are implicated in a wide array of cancers including breast cancer. Specifically, Rab25, a GTPase associated with the recycling endosomes, is deregulated in most epithelial cancers. Rab25 appears to function both as a tumor suppressor and an oncogene in a context dependent manner. We found that Rab25 is lost in Claudin Low tumors as well as in representative cell lines such as the MDA MB231. Rab25 is a robust and sufficient marker of breast cancers and cell lines with an increased EMT signature. Additionally, in immortalized human mammary epithelial cell lines (HMLE), induction of EMT by overexpression of Snail1 completely obliterates Rab25 protein. Exogenous re-expression of Rab25 dramatically rescues these cells from Snail driven invasion through Matrigel. However this Snail dependent regulation is unique only to TN and Claudin Low tumors and does not hold true for hormone receptor positive tumors. Further, analysis of RNA Seq data from a MMTV mouse model showed that tumors enriched in EMT markers and by corollary with low CDH and claudins, also lost Rab25 transcripts. Snail mediated Transcriptional repression targets recycling endosomal proteins such as Rab25 to decrease delivery of junction proteins that facilitate cell-cell communication to the appropriate compartment. In parallel, it potentially enhances paracrine regulation by secreted exosomes. Overall, our study shows presence and absence of Rab25 markedly alters cell-cell communication, which is essential for maintenance of epithelial features of cells. Rab25 could be a prognostic marker and a therapeutic target for a subset of patients with increased risk of metastatic disease. Citation Format: Shreya Mitra, Lorenzo Federico, Gordon B. Mills. Transcription Factor Snail mediates EMT by altering vesicular trafficking protein Rab25. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B40.

  • abstract 4040 Transcription Factor Snail mediates emt by altering vesicular trafficking protein rab25
    2015
    Co-Authors: Shreya Mitra, Lorenzo Federico, Tapashree Roysarkar, Sendurai A Mani, Gordon B Mills
    Abstract:

    Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Epithelial cells maintain intercellular communication directly by cell-cell, cell-ECM interaction and indirectly by paracrine secretion of extracellular messengers either as free molecules or via exosomes. The vesicular trafficking machinery is an integral part of such communication, paralleling digital cables that transmit the information bytes to the correct hub. During the process of EMT, derailing of the trafficking machinery leads to a systemic breakdown of intra and inter-cellular communication pathways. The purpose of the current study is to elucidate the functional role of Rab25, a key member of the vesicular trafficking machinery in mediating EMT-MET processes during breast cancer progression. Aberrant endocytosis is a new hallmark of cancer. Rab GTPases are the primary regulators of endocytosis. Many members of this large family are implicated in a wide array of cancers including breast cancer. Specifically, Rab25, a GTPase associated with the recycling endosomes, is deregulated in most epithelial cancers. Rab25 appears to function both as a tumor suppressor and an oncogene in a context dependent manner. We found that Rab25 is lost in Claudin Low tumors as well as in representative cell lines such as the MDA MB231. Rab25 is a robust and sufficient marker of breast cancers and cell lines with an increased EMT signature. Additionally, in immortalized human mammary epithelial cell lines (HMLE), induction of EMT by overexpression of Snail1 completely obliterates Rab25 protein. Exogenous re-expression of Rab25 dramatically rescues these cells from Snail driven invasion through MatrigelTM. However this Snail dependent regulation is unique only to TN and Claudin Low tumors and does not hold true for hormone receptor positive tumors. Further, analysis of RNA Seq data from a MMTV mouse model showed that tumors with low CDH1/Claudins expression and enriched in EMT markers also lost Rab25 transcripts. Snail mediated Transcriptional repression targets recycling endosomal proteins such as Rab25 to decrease delivery of junction proteins that facilitate cell-cell communication to the appropriate compartment. In parallel, it potentially enhances paracrine regulation by secreted exosomes. Overall, our study shows presence and absence of Rab25 markedly alters cell-cell communication, which is essential for maintenance of epithelial features of cells. Rab25 could be a prognostic marker and a therapeutic target for a subset of patients with increased risk of metastatic disease. Note: This abstract was not presented at the meeting. Citation Format: Shreya Mitra, Lorenzo Federico, Tapashree Roysarkar, Sendurai Mani, Gordon B. Mills. Transcription Factor Snail mediates EMT by altering vesicular trafficking protein Rab25. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4040. doi:10.1158/1538-7445.AM2015-4040