Small proline-rich proteins (SPRR) function as SH3 domain ligands, increase resistance to injury and are associated with epithelial–mesenchymal transition (EMT) in cholangiocytes

Demetris, Anthony J.; Specht, Susan; Nozaki, Isao; Lunz, John G.; Stolz, Donna B.; Murase, Noriko; Wu, Tong

doi:10.1016/j.jhep.2007.09.019

Cited by 36 publications

(60 citation statements)

References 60 publications

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“…Small proline rich protein 2a (SPRR2a) overexpression in CCA cells induced EMT, which in turn promotes invasiveness [59,120]. Further experiments showed that SPRR2A acts as a transcriptional corepressor with ZEB1 to repress miR-200c/141 transcription in CCA cells in order to maintain a mesenchymal phenotype [59].…”

Section: Additional Regulatory Factorsmentioning

confidence: 99%

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

113

122

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Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT. 4Key Point Box -EMT is an early event of metastasis that endows tumor cells with invasive properties enabling them to spread toward other territories.-EMT contributes to CCA progression and chemoresistance.-The three families of transcription factors that regulate epithelial and mesenchymal marker expression during EMT (SNAIL, TWIST and ZEB) contribute to CCA progression.-Cells of CCA microenvironment, and not only cancer cells, lead to the activation of EMT.

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Section: Additional Regulatory Factorsmentioning

confidence: 99%

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Vaquero

Guedj

Clapéron

et al. 2017

Journal of Hepatology

113

122

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“…EMT is a complex process that involves cross talk among several signaling pathways that collaborate to affect global, but gradual, changes in cell structure and function [56] . In this dynamic process cells eventually lose their typical epithelial characteristics (proteins that mediate cell-cell, cell-matrix contacts and cytoskeletal organization) [57,58] . These changes cause epithelial cells to disassociate from their neighbors, gradually acquire a motile phenotype, and eventually migrate out of epithelial sheets and into adjacent mesenchyme [21,56] .…”

Section: Epithelial-to-mesenchymal Transition (Emt)mentioning

confidence: 99%

Involvement of cholangiocyte proliferation in biliary fibrosis

Priester

Wise²,

Glaser

2010

WJGP

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Cholangiocytes are the epithelial cells that line the biliary tree. In the adult liver, they are a mitotically dormant cell population, unless ductular reaction is triggered by injury. The ability of cholangiocytes to proliferate is important in many different human pathological liver conditions that target this cell type, which are termed cholangiopathies (i.e. primary biliary cirrhosis, primary sclerosing cholangitis and biliary atresia). In our article, we provide background information on the morphological and functional heterogeneity of cholangiocytes, summarize what is currently known about their proliferative processes, and briefly describe the diseases that target these cells. In addition, we address recent findings that suggest cholangiocyte involvement in epithelialtomesenchymal transformation and liver fibrosis, and propose directions for future studies.

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“…The process of EMT has received great attention and its role in kidney fibrosis has been studied extensively in recent years 13,14 . Moreover, the EMT concept has been successfully translated to liver fibrogenesis 15–21 . Especially in cholestatic liver diseases and their corresponding animal models EMT, namely from bile duct epithelial cells into myofibroblasts, is supposed to play a pivotal role in the initiation and perpetuation of liver fibrosis 15,17 .…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the EMT concept has been successfully translated to liver fibrogenesis 15–21 . Especially in cholestatic liver diseases and their corresponding animal models EMT, namely from bile duct epithelial cells into myofibroblasts, is supposed to play a pivotal role in the initiation and perpetuation of liver fibrosis 15,17 . As such, previous studies in the DDC-fed mouse model showed pronounced induction of hepatic OPN in BECs (including BECs in reactive ductules) and hepatocytes in acinar zone 1 according to those lobular regions where adjacent porto-portal septa develop in later in the disease course 6 .…”

Section: Introductionmentioning

confidence: 99%

The role of osteopontin and tumor necrosis factor alpha receptor-1 in xenobiotic-induced cholangitis and biliary fibrosis in mice

Fickert

Thueringer

Moustafa

et al. 2010

Laboratory Investigation

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Background & Aims Proinflammatory and profibrotic cytokines such as osteopontin (OPN) and tumor necrosis factor-alpha receptor 1 (TNFR1) may be critically involved in the pathogenesis of cholangiopathies and biliary fibrosis. We therefore aimed to determine the role of genetic loss of either OPN or TNFR1 in 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice as a model of xenobiotic-induced sclerosing cholangitis with biliary-type liver fibrosis using respective knock-out mice. Methods OPN and TNFR1 knock-out mice were fed a 0.1% DDC-supplemented diet for 4 weeks and compared to corresponding wild type (WT) controls. Liver morphology (H&E staining), serum markers of liver injury and cholestasis (ALT, AP, bilirubin), markers of inflammation in liver (CD11b and F4/80 immunostaining, mRNA expression of iNOS, MCP-1, IL-1β, INF-γ, TNF-α, and OPN), degree of ductular reaction (immunohistochemistry with morphometric analysis and Western blotting for cholangiocyte specific marker keratin 19) and degree of liver fibrosis (Sirius red-staining, hepatic hydroxyproline content for quantification) were compared between groups. Results DDC feeding in OPN and TNFR1 knock-out mice and respective WT controls resulted in comparable extent of liver injury, inflammatory response, ductular reaction, and liver fibrosis. Summary & Conclusions Our data indicate that genetic loss of neither OPN nor TNFR1 significantly impacts on the pathogenesis of DDC-induced sclerosing cholangitis, ductular reaction and resulting biliary fibrosis.

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Small proline-rich proteins (SPRR) function as SH3 domain ligands, increase resistance to injury and are associated with epithelial–mesenchymal transition (EMT) in cholangiocytes

Cited by 36 publications

References 60 publications

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Epithelial-mesenchymal transition in cholangiocarcinoma: From clinical evidence to regulatory networks

Involvement of cholangiocyte proliferation in biliary fibrosis

The role of osteopontin and tumor necrosis factor alpha receptor-1 in xenobiotic-induced cholangitis and biliary fibrosis in mice

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