The expression of epithelial–mesenchymal transition–related proteins in biliary epithelial cells is associated with liver fibrosis in biliary atresia

Xiao, Yongtao; Zhou, Ying; Chen, Yingwei; Zhou, Kejun; Wen, Jie; Wang, Yang; Wang, Jun; Cai, Wei

doi:10.1038/pr.2014.181

Cited by 36 publications

(22 citation statements)

References 20 publications

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“…[28][29][30][31][32] Expression of a-SMA correlates with the extent of fibrosis in BA. 21,29,30,33,34 and increased expression of a-SMA at PE predicts impaired outcome. 21,29,31,35 Accordingly, we found portally concentrated periductal a-SMA expression patterns, which tended to persist after SPE.…”

Section: Discussionmentioning

confidence: 99%

Molecular signature of active fibrogenesis prevails in biliary atresia after successful portoenterostomy

Kerola

Lampela

Heikkilä

et al. 2017

Surgery

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Section: Discussionmentioning

confidence: 99%

Molecular signature of active fibrogenesis prevails in biliary atresia after successful portoenterostomy

Kerola

Lampela

Heikkilä

et al. 2017

Surgery

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“…Here, overexpression of MMP-7 and CK-7 shared similar patterns in ductal proliferation and in periportal hepatocytes, suggesting that MMP-7 is involved with hepatic tissue remodeling by ductal proliferation in BA. MMP-7 is able to cleave extracellular matrix and basement membrane, while ductal proliferation may drive fibrogenesis through epithelial-tomesenchymal metaplasia [8,9,12,14,17,40].…”

Section: Mmp-7 Expression In Biliary Epithelial Cells Andmentioning

confidence: 99%

Increased MMP‐7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia

Kerola

Lampela

Lohi

et al. 2016

The Journal of Pathology CR

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The molecular mechanisms underlying progressive liver fibrosis following surgical treatment of biliary atresia (BA) remain unclear. Our aim was to address hepatic gene and protein expression and serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) after successful portoenterostomy (PE), and relate them to histological signs of liver injury, clinical follow‐up data and biochemical markers of hepatic function. LIver biopsies and serum samples were obtained from 25 children after successful PE at median age of 3.3 years. Serum MMP concentrations were determined by enzyme‐linked immune sorbent assay. Hepatic gene expression of MMPs and TIMPs was analyzed using real‐time reverse‐transcription PCR. Liver expression of MMP‐7 and cytokeratin‐7 was studied using immunohistochemistry. Despite effective clearance of biochemical and histological cholestasis following PE, BA patients showed increased hepatic gene expression of MMP‐7 (29‐fold, p < 0.001), MMP‐2 (3.1‐fold, p < 0.001), MMP‐14 (1.7‐fold, p = 0.007), and TIMP‐1 (1.8‐fold, p < 0.001), when compared to controls. Similar to a biliary epithelial marker cytokeratin‐7, expression of MMP‐7 localized in biliary epithelium of bile ducts and ductal proliferations and periportal hepatocytes and was increased (p < 0.001) in relation to controls. BA patients had 6‐fold higher serum levels of MMP‐7 (p < 0.001), which correlated positively with hepatic MMP‐7 gene (r = 0.548, p = 0.007) and protein (r = 0.532, p = 0.007) expression. Patients showed a positive correlation between biliary MMP‐7 expression and Metavir fibrosis stage (r = 0.605, p = 0.001) and portal fibrosis grade (r = 0.606, p = 0.001). Neither similarly increased MMP‐7 expression nor correlation with liver fibrosis was observed in patients with intestinal failure‐associated liver disease and comparable Metavir stage. In conclusion, our findings support an unique role of altered hepatic expression of MMP‐7 in the progression of liver fibrosis after successful PE and introduce a potential therapeutic target to pharmacologically extend native liver survival by inhibiting MMP‐7 hyperactivity. Serum MMP‐7 may be a valuable postoperative prognostic tool in BA.

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“…It has been demonstrated that the hepatocyte-derived myofibroblast subpopulation is positive for fibroblastspecific protein 1 (FSP-1), whereas MFB derived from HSC are positive for α-smooth muscle actin [123]. Likewise, bile-duct epithelial cells can contribute to the MFB population, since these cells express EMT markers associated with bile duct ligation and bile duct atresia in humans [123,126].…”

Section: Purinergic Signaling Emt and Fibrosismentioning

confidence: 99%

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

Martinez-Ramirez

Dı́az-Muñoz

Butanda-Ochoa

et al. 2016

Purinergic Signalling

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The epithelium-mesenchymal transition (EMT) is an important process of cell plasticity, consisting in the loss of epithelial identity and the gain of mesenchymal characteristics through the coordinated activity of a highly regulated informational program. Although it was originally described in the embryonic development, an important body of information supports its role in pathology, mainly in cancerous and fibrotic processes. The purinergic system of inter-cellular communication, mainly based in ATP and adenosine acting throughout their specific receptors, has emerged as a potent regulator of the EMT in several pathological entities. In this context, cellular signaling associated to purines is opening the understanding of a new element in the complex regulatory network of this phenotypical differentiation process. In this review, we have summarized recent information about the role of ATP and adenosine in EMT, as a growing field with high therapeutic potential.Keywords P2 receptors . P1 receptors . Purinergic signaling . Cell migration . EMTThe purinergic system of intercellular communication General aspects The term purine (from: pure urine) was created more than 130 years ago by Emil Fischer after detailed analytical characterization of the uric acid molecule [1]. Purine molecular structure is the result of fusing pyrimidine and imidazole rings, and it exists as four N-H tautomeric forms [2]. Tautomerism of purine bases in DNA is one of the earliest reasons for mutations [3][4][5]. The interconversion of the different adenine or guanine tautomers produced mispairing with pyrimidines (which also show tautomeric forms) that may lead to changes in DNA sequence [6].Purine molecules appeared very early in the history of our planet, in the period known as Borganic evolution^, before the establishment of living systems. It has been postulated that purines could be formed by a eutectic (denoting a mixture of substances in fixed proportions that melts and freezes at a single temperature that is lower than the melting points of any of the separate constituents) concentration of HCN at extremely low temperature over a period of dozens of years [7]. Purine molecules, such as adenine and guanine, are components of the genetic material (DNA and RNA) of all living beings. Purine and pyrimidine tautomeric equilibria in nucleic acids was postulated to be significant in events such as DNA replication and repair as well as in the occurrence of point mutations [8].As nucleosides and nucleotides, purines play other highly strategic roles, acting as energy intermediates, allosteric regulators of key metabolic activities, redox molecules, and chemical messengers for signal transduction events. The two most important purines serving as extracellular ligands for paracrine and autocrine signaling are ATP and its dephosphorylated form, adenosine (ADO). ATP and ADO act as intracellular intermediate metabolites, and their presence in the

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The expression of epithelial–mesenchymal transition–related proteins in biliary epithelial cells is associated with liver fibrosis in biliary atresia

Cited by 36 publications

References 20 publications

Molecular signature of active fibrogenesis prevails in biliary atresia after successful portoenterostomy

Molecular signature of active fibrogenesis prevails in biliary atresia after successful portoenterostomy

Increased MMP‐7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia

Nucleotides and nucleoside signaling in the regulation of the epithelium to mesenchymal transition (EMT)

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