Bile duct epithelial tight junctions and barrier function

Rao, Radhakrishna; Samak, Geetha

doi:10.4161/tisb.25718

Cited by 55 publications

(36 citation statements)

References 99 publications

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“…Furthermore, SOX17 also downregulated the expression of some genes involved in proliferation and inhibited the anchorage-independent growth and the invasion/migration capacity of CCA cells; this fact was associated with downregulation of different proinvasive/migration genes including S100A4 , which is a key driver for CCA dissemination [24]. The analysis of the biliary phenotype in CCA cells revealed that SOX17 stimulates the expression of the biliary marker CK7 and epithelial markers FN and ZO-1 , whose deficiency has been related to cancer progression [25]. Moreover, SOX17 normalizes the upregulated CK19 expression in CCA cells.…”

Section: Discussionmentioning

confidence: 99%

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

Merino-Azpitarte

Lozano

Perugorria

et al. 2017

Journal of Hepatology

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Background & aims Cholangiocarcinoma (CCA) is a biliary malignancy linked to genetic and epigenetic abnormalities, such as hypermethylation of SOX17 promoter. Here, the role of SOX17 in cholangiocyte differentiation and cholangiocarcinogenesis was studied. Methods SOX17 expression/function was evaluated along the differentiation of human induced pluripotent stem cells (iPSC) into cholangiocytes, in the dedifferentiation process of normal human cholangiocytes (NHC) in culture and in cholangiocarcinogenesis. Lentiviruses for SOX17 overexpression or knock-down were used. Gene expression and DNA methylation profiling were performed. Results SOX17 expression is induced in the last stage of cholangiocyte differentiation from iPSC and regulates the acquisition of biliary markers. SOX17 becomes downregulated in NHC undergoing dedifferentiation; experimental SOX17 knock-down in differentiated NHC downregulated biliary markers and promoted baseline and Wnt-dependent proliferation. SOX17 expression is lower in human CCA than in healthy tissue, which correlates with worse survival after tumor resection. In CCA cells, SOX17 overexpression decreased their tumorigenic capacity in murine xenograft models, which was related to increased oxidative stress and apoptosis. In contrast, SOX17 overexpression in NHC did not affect their survival but inhibited their baseline proliferation. In CCA cells, SOX17 inhibited migration, anchorage-independent growth and Wnt/β-catenin-dependent proliferation, and restored the expression of biliary markers and primary cilium length. In human CCA, SOX17 promoter was found hypermethylated and its expression inversely correlates with the methylation grade. In NHC, Wnt3a decreased SOX17 expression in a DNMT-dependent manner, whereas in CCA, DNMT1 inhibition or silencing upregulated SOX17. Conclusions SOX17 regulates the differentiation and maintenance of the biliary phenotype and functions as a tumor suppressor for CCA, being a potential prognostic marker and a promising therapeutic target.

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Section: Discussionmentioning

confidence: 99%

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

Merino-Azpitarte

Lozano

Perugorria

et al. 2017

Journal of Hepatology

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“…The loss of function of TJ proteins is not lethal and the clinical manifestation is variable including very mild symptoms 102. A comprehensive description of TJ protein alterations in biliary diseases is reviewed in ref 97.…”

Section: Tj Proteins and The Gi Tractmentioning

confidence: 99%

Tight junction proteins in gastrointestinal and liver disease

Zeisel

Dhawan

Baumert

2018

Gut

229

179

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Over the past two decades a growing body of evidence has demonstrated an important role of tight junction (TJ) proteins in the physiology and disease biology of GI and liver disease. On one side, TJ proteins exert their functional role as integral proteins of TJs in forming barriers in the gut and the liver. Furthermore, TJ proteins can also be expressed outside TJs where they play important functional roles in signalling, trafficking and regulation of gene expression. A hallmark of TJ proteins in disease biology is their functional role in epithelial-to-mesenchymal transition. A causative role of TJ proteins has been established in the pathogenesis of colorectal cancer and gastric cancer. Among the best characterised roles of TJ proteins in liver disease biology is their function as cell entry receptors for HCV—one of the most common causes of hepatocellular carcinoma. At the same time TJ proteins are emerging as targets for novel therapeutic approaches for GI and liver disease. Here we review our current knowledge of the role of TJ proteins in the pathogenesis of GI and liver disease biology and discuss their potential as therapeutic targets.

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“…It is likely that alterations of bile ducts occur through mechanosensation and consequent Ca 2+ /cyclic adenosine monophosphate signaling, rather than due to purely physical effects of increased biliary fluid pressure. Other signaling pathways stimulated by BS cause actin and tight junction remodeling that may explain the leakiness of the biliary tree …”

Section: The Role Of Intraluminal Biliary Pressurementioning

confidence: 99%

“…Other signaling pathways stimulated by BS cause actin and tight junction remodeling that may explain the leakiness of the biliary tree. (28,29,59,60) If biliary pressure plays a role, this will be most relevant for extrahepatic obstruction and PSC, anatomically characterized by bile duct dilatation and beading of the biliary tree. However, despite the evolution of knowledge on possible control mechanisms, a molecular link between either biliary pressure or bile constituents in cholestasis on the periductular cytoskeleton and associated transporter functions has not yet been demonstrated.…”

Section: > < >mentioning

confidence: 99%

The ascending pathophysiology of cholestatic liver disease

Ghallab²,

et al. 2017

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In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ascending course of the disease process. The first and early lesions are in “downstream” bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)–mediated toxic injury of the “upstream” liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom‐poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%‐60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more “tailored” use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium‐dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis–suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti‐inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor‐ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end‐stage disease. These are arguments to consider a step‐wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage–defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722‐738).

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Bile duct epithelial tight junctions and barrier function

Cited by 55 publications

References 99 publications

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma

Tight junction proteins in gastrointestinal and liver disease

The ascending pathophysiology of cholestatic liver disease

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