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International Journal of Cancer and Clinical Research





DOI: 10.23937/2378-3419/1410079



The Role of Notch Signaling in Liver Diseases: Contribution to Development and Cancer

Kazunori Kawaguchi, Masao Honda* and Shuichi Kaneko


Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Japan


*Corresponding author: Masao Honda, MD, PhD, Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa, Ishikawa 920-8641, Japan, Tel: +81-76-265-2233, Fax: +81-76-234-4250, E-mail: mhonda@m-kanazawa.jp
Int J Cancer Clin Res, IJCCR-4-079, (Volume 4, Issue 1), Review Article; ISSN: 2378-3419
Received: February 23, 2017 | Accepted: March 29, 2017 | Published: March 31, 2017
Citation: Kawaguchi K, Honda M, Kaneko S (2017) The Role of Notch Signaling in Liver Diseases: Contribution to Development and Cancer. Int J Cancer Clin Res 4:079. 10.23937/2378-3419/1410079
Copyright: © 2017 Kawaguchi K, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



Abstract

Liver tissue consists of several types of cells such as hepatocytes, endothelial cells, stellate cells, cholangiocytes, and immune cells, all with essential functions. The liver plays an important role in metabolism because its cells act on a variety of substances, transforming them into metabolic products essential for life and the production of waste products. One interaction between different adjacent cells is known as Notch signal transduction, and abnormalities in this signaling pathway can cause serious liver diseases including inherited diseases and cancer that sometimes exhibit aggressive phenotypes and have poor prognoses. Moreover, over activation of Notch signaling is associated with tumorigenesis and linked to the development of cancer stem cells. Here, we review the association between liver diseases and Notch signaling abnormalities related to signal transduction in the liver and the development of hepatocytes or cholangiocytes.


Keywords

Notch, Jagged, DLL, HES, NICD


Introduction

Liver diseases have a diverse range of etiologies including infections, such as hepatitis A to E, cytomegalovirus, and Epstein-Barr virus, non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver diseases (NAFLD), and alcoholic liver injury or fibrosis. In addition, primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are immune-mediated, while Wilson's disease and Alagille syndrome, which exhibit severe liver dysfunction, are inherited. Furthermore, drug-induced liver injury is a common cause of abnormal elevation of transaminase. These liver diseases are detected by abnormal pathological findings in the liver tissue, for example, advanced liver disease may show severe fibrosis and inflammation in a specific area, and extra hepatic abnormalities such as portal hypertension, systemic edema, as cites, and jaundice. Lymphocyte infiltration can be seen in the portal triad area in viral hepatitis, and around the central vein area in a congestive liver. These infiltrating cells consist of hepatocytes and in the case of cancer, hepatoma cells and occasionally cancer stem cells and non-liver parenchymal cells. These include lymphocytes, stellate cells, endothelial cells, macrophages, and cholangiocytes. These cells each have essential functions and there may be functional and signaling interactions between adjacent cells, regardless of cell type. Thus, to clarify the mechanisms of liver diseases, it is crucial to observe both the functions of the individual cell types and how the different types of cells interact, for example, the interactions between hepatocytes and stellate cells, hepatocytes and endothelial cells, and hepatocytes and lymphocytes. These interactions are associated with specific signal transductions such as Wnt/β-catenin signaling, and MAPK and IFN signaling. Notch signaling is reportedly associated with signal transduction in these cells and in the development of liver cells. Furthermore, abnormalities in a ligand in the Notch signaling pathway, known as the Jagged1 gene, leads to Alagille syndrome, which is a well-known liver disease. This syndrome displays hypoplasia of cholangiocytes and systemic abnormalities in other organs, such as the lungs and bodies of the vertebrae. However, recent research has revealed Notch-related abnormalities in other liver diseases such as liver cancer and steatosis. Therefore, Notch signaling is closely associated with liver diseases as well as the physiological functions of the liver. Here, we introduce the association between Notch signaling and various liver diseases with reference to the literature.


Notch Signaling and the Functions of Component Molecules

Notch signaling is mainly associated with cell-cell signal transduction to adjacent cells, and is not a form of communication between remote cells. There are several Notch transduction ligands, such as Jagged1, Jagged2, DLL1, DLL3, and DLL4, and receptors such as Notch1, Notch2, Notch3, and Notch4 [1]. In 1913, Notch signaling was discovered by observing a notch-like defect in the wings of Drosophila and the phenotype was named "Notch" [2]. In the 1930s, a homozygote Notch mutation was found not in the epidermidis but in nerve tissues, which suggested that Notch expression is related to the formation of neurogenic factors [3]. Notch-related genes were cloned and sequenced for the first time in 1985, revealing that Notch is a transmembrane receptor with extracellular and intracellular domains [4,5]. The Notch receptor and ligand were also found later in Drosophila. However, although many Notch-related factors including ligands and receptors have been discovered, their exact functions have not been clarified [1]. Research conducted on C. elegans discovered a Notch homolog and found that Presenilin1 (PSEN1) is an essential factor for Notch activation [6-8]. Thereafter, it was discovered that the function of PSEN1 is to cut the transmembrane protein, and gamma secretase was found to act as catalyst at the transmembrane region of Notch. Kopan, et al. found that the Notch intracellular domain (NICD) translocates to the nucleus and activates the expression of the target gene, while removal of the signal results in loss of the gene's function [9]. This discovery was associated with Notch signaling in that the receptor, such as Notch1, was activated by contacting the ligand of adjacent cells such as Jagged1, cut by gamma secretase, and NICD was transported to the nucleus directory to regulate downstream gene transcription. Furthermore, NICD is transported to the nucleus and binds to Su(H)/RBPj and p300 as a histone accessory factor. HES or HEY family genes are activated as downstream genes [10,11]. After these genes are transcribed, NICD undergoes proteasomal degradation with phosphorylation by Cdk8, poly-ubiquitination by Fbxw7, resulting in the termination of signal activation [12]. Glycosylation is another phenomenon of Notch signaling, which is important for the modulation of signaling [13,14]. Notch is glycosylated by rumi or POGLUT1 and fucosylated by O-FUT1 or POFUT1. The glycosylic chain of the fucosylated Notch is elongated at the Golgi apparatus by Fringe, LFNG, MFNG, and RFNG. These enzymes are glycosyl chain elongation enzymes in addition to fucose and GLcNAc. Fringe-modified Notch is affected by D1/DLL but not Ser/JAG, and the non-fringe modified form is affected by Ser/JAG but not D1/DLL. Therefore, Notch activation differs depending on the type of ligand and receptor, and these indicate whether there is fringe or not [15,16].

Whether there are sufficient adjacent interactions between Notch ligands and receptors is also important, and is has been found in Drosophila studies that receiving cells such as Notch receptors rely on dynamin to perform endocytosis [16]. This is adjusted by ubiquitin E3 ligase, which codes mind bomb 1 (mib1), resulting in an association with amino acid that is sensitive to ADAM protease. Notch receptor at the transmembrane is first processed by ADAM protease and that changes to NEXT (Notch extracellular truncation), before processing to NICD (S3 cleavage) by gamma secretase complex [17]. Therefore, Notch activation-related factor is not a ligand or receptor as described above, and its signaling does not have an amplifying effect in receiving cells; adistinct mechanism from other types of signal transduction. This indicates that the intensity of the Notch signal between cells is affected by the amount of Notch receptor transcription, accessory factor patterns, amount of expression and binding, amount of endocytosis of the ligand-receptor complex, and level of S2 and S3 cleavage [18], instead of simply by signal amplification a single cell.

The role of Notch signaling is associated with the generation of more than two types of cells from uniform cells types. There are several mechanisms that can achieve this, such as lateral inhibition, asymmetric cell division, lineage decisions, and induced signaling [19,20]. Lateral inhibition by Notch activation results in a decrease in Notch ligand expression [21]. This generates two types of Notch-off cells and Notch-on cells patterns. When observing asymmetric cell division, a cell duplicates, and in one duplicates Notch is activated, and in the other it is not, leading to different cell fates, and is also asymmetrically distributed by the interaction of the cell polarization molecule and endoplasmic reticulum transportation in cells [22]. The induction of Notch signaling causes activation by one-sided signaling of ligand-expressing cells and signaling is dependent on the type of Notch receptor and the Fringe.


Notch Signaling Abnormalities and Diseases Related to Development

Molecular research into Notch signaling has developed through the analysis of Drosophila and C. elegans; however, this is insufficient for the analysis and discovery of Notch signaling related molecules in mammalian cells. On the other hand, this research has resulted in the discovery of Notch-related essential molecules in mammalian cells in mice and humans. Neural development-related studies using a mouse model have led to rapid progression in the field [23,24]. Alagille syndrome is a well-known autosomal dominant Notch-related inherited disease in humans [25-27], and causes cholestasis by decreasing the numbers and functions of the bile duct cells and causing chronic liver injury. Furthermore, abnormalities of the heart and blood vessels, vertebrae, eyes, and specific facial characteristics may occur. The disease was discovered in 1969 by Alagille, and patients with all five of the characteristic abnormalities are known as "complete types", while those with four are known as "incomplete types" [28-30]. In 1997, the discovery of a Jagged1 genomic abnormality at 20q was reported [27,31-33]. In 2006, a Notch2 genomic abnormality was also reported [34]. The population frequency of Alagille syndrome is 1 per 30,000 to 70,000 and ulsodeoxy-acid, and cholestyramine is used to control bile acid metabolism in cholestasis patients. However, if liver cirrhosis occurs, transplantation may be considered. Nutritional therapy with lipid soluble vitamins and medium chain fatty acids may also be considered [35,36].

It has been reported that a Notch1 mutation is associated with inherited heart diseases [37]. This mutation is especially linked to the bicuspid aortic valve and calcification of the aorta [38,39]. Moreover, it is associated with the tetralogy of Fallot, which encompasses pulmonary artery stenosis, ventricular septal defect (VSD), over-riding aorta, and right ventricular hypertrophy. Mutations of Jagged1 and Notch2 gene cause Alagille syndrome and tetralogy of Fallot [40,41]. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant inherited disease that causes cerebral infarction and angiogenic dementia [42-45]. This disease is reported to be associated with a Notch3 mutation which results in the extracellular domain of Notch3 accumulating in the cerebral micro vessels.

The relationship between Notch signaling and heart vessels reportedly includes stages of development from bone marrow cells to endothelial cells during fetal life, and Notch signaling facilitates inflammation and induces senescence of endothelial cells, resulting in atherosclerosis [46,47]. These reactions are reported to involve macrophages [48]. For example, antigen-presenting cells that express DLL1 or DLL4 cause accelerated differentiation to Th1 cells. Th1 and Th1 cytokines accelerate inflammation of the heart vessels. However, Jagged1accelerates differentiation to Th2 cells, which suppresses inflammation in the heart vessels [49,50]. Dll4-Notch signaling enhances plaques and fibroblast collagen and calcification in vessels, up regulates insulin resistance, increases the amount of fat cells, and promotes fatty liver by the deposition of fat in the liver, resulting in fatty liver diseases including NAFLD or NASH [51,52]. DLL4 antibody is reported to suppress M1 macrophages [53] and experiments have shown that it induces inflammation via mediators such as iNOS, which is atypical M1 macrophage mediator [48]. The study also showed that M1 macrophage polarization related to DLL4 antibodies could be a candidate for various diseases related to inflammation, including in the heart vessels and organs related to metabolism.


Differentiation of Hepatocytes or Cholangiocytes by Notch Signaling and Liver Diseases

Alagille syndrome has characteristic ductal loss that indicates hypoplasticity in the bile ductal cells. This is because of a loss of Notch transduction function caused by a Jagged1 mutation. However, Notch signaling is involved only in the bile ducts in this disease. A previous report has shown that Notch contributes to the formation of intrahepatic cholangiocarcinoma (ICC) arising from the conversion of hepatocytes rather than cholangiocytes activated by Notch [54]. This indicates that Notch signaling activates malignant characteristics in hepatomas and ICC. Liver cancer has been reported especially frequently, even among other hepatomas. Reports suggest that RUNX3 is associated with the suppression of liver cancer, and that Jagged1 gene and RUNX3 are associated [55,56]. We previously analyzed clinical samples and showed that Jagged1 genomic amplification and over expression in AFP-producing cells is associated with liver cancer, as well as the malignant characteristics of cancer and overall survival [57]. Jagged1 is reportedly associated with upstream YAP and Hippo signaling. Moreover, gamma secretase inhibitors (GSIs) are effective angiogenetic factors of liver cancer [58-60]. Liver tumorigenesis caused by hepatitis B virus (HBV) is associated with the HBV-x genes directory or disease progression [61-65], and the HCV core protein is regulated by gamma secretase, which regulates Notch signaling [66,67]. Liver cancer is mainly associated with stemness and Notch regulation is associated with stem cell differentiation [68], and POGLUT 1 copy number variations [69,70]. Furthermore, DLL-Notch pathway is associated with liver fibrosis and M2 macrophage activation [51,71,72]. Conversely, M1 macrophages are associated with alcoholic liver injury via Notch signaling [73,74]. Some liver cancers are associated with angiogenesis, which is regulated by Ephrin [75] and in turn regulated by GSIs [76], which decrease hepatoma cells, especially α-protein (AFP)-upregulated cells. Blocking of notch signaling components such as Jagged1 shRNA results in an effective decrease of AFP-upregulating hepatoma cells [57]. Thus, gamma secretase may be a target for liver cancer therapy, although the phenotype might be restricted. Fibrosis-related Notch signaling abnormalities in liver diseases are important for liver cancer research because many liver cancers have a background of progressive fibrosis and inflammation, and these microenvironments are closely associated with tumorigenesis cancer formation and more aggressive carcinogenic characteristics. This phenomenon can result in Notch transduction abnormalities between adjacent but different types of cells.


Function of Notch Signaling Related Molecules and the Liver

The association between Notch signaling and liver tissue is introduced in relation to the development of hepatocytes and cholangiocytes, including progenitor cells that include cancer-related cells. We have introduced the functions of Notch ligand and receptors, showing that each molecule has a different function, and the different functions lead to different types of diseases (Table 1). Notch1 is associated with the tumorigenicity of hepatocytes, and biliary differentiation from HPCs is controlled by autophagy [77,78]. Notch2 is associated with developmental retardation and bile duct development, since this defect results in hypogenesis of cholangiocytes. Moreover, Notch2 is associated with the aggressiveness of liver cancer and hepatoblastoma [79-82]. Notch3 drives the differentiation and progression of cholangio carcinoma [83]. However, the relationship between its activation levels and liver cancer has not been defined, although it is reported to modulate the stemness of tumor cells [84]. Notch4 induces reversible arteriovenous malformation and this deficiency results in angiogenesis, vascular remodeling, and hepatocyte-lineage-HPCs, resulting in tumorigenesis [85-88].



Table 1: Roles of notch ligands and receptors associated with liver diseases, especially liver cancer. View Table 1


Yang, et al. reported Notch1, Notch3, and Notch4 up regulation is associated with liver cancer involving HBV-x protein [61,86]. As Notch ligands, Jagged1 mutations or defects constitute the pathogenesis of Alagille syndrome, while Jagged2 is not usually related to hepatocytes or liver tissue. Though DLL1 defects stimulate neuronal differentiation and severe somite patterning defects, reports on their relationship to the liver are scarce. Moreover, while DLL3 defects produce abnormalities in somitogenesis and autosomal recessive spondylocostal dysostosis, they show little association with liver diseases [89]. DLL4 defects exhibit arteriovenous shunting and severe vascular remodeling defects, and the molecule has been reported many times in relation to liver diseases such as liver cancer, NASH, and HBV-x related tumorigenesis [76,90,91]. These results indicate that Notch-related ligands and receptors produce loss of organ or tissue formation, especially in vascular tissue, bile ducts, and neurons.

Notch activation is associated with liver cancer and this triggers epithelial-mesenchymal transformation promoting the self-renewal of cancer stem-like cell niches in primary and monastic tumors. In chronic HBV infection, the repression of Notch receptors in chronic hepatitis B (CH-B) patients is suggested to repress immune regulation, which results in the inhibition of differentiation and the proliferation of effect or cells, consequently leading to further pathogenesis [92]. The pro-oncogene function ofmastermind2 (MAML2) is to target genetic alterations in various types of cancer, and it is associated with Notch activation even in hepatobiliary neoplasms [93-95]. Genetic analysis has shown that mice over expressing NICD represent a cluster of liver cancers [96]. Notch2 over expression causes HPCs to spontaneously develop into dedifferentiated liver cancer cells [97] and Notch-induced malignant hepatocyte transformation is associated with down regulation of hepatocyte-associated genes, including Sox9 [98]. In the development of cholangio carcinoma, NICDs associated with protein kinase B signaling stimulates the malignant differentiation of hepatocytes [99].


Notch Inhibition is Effective for Liver Cancer Treatment

Most reports showed that Notch signaling is enhanced in mouse cancer models and inhibition results in a reduction in tumor size. Moreover, Notch activation is reported to result in a more malignant phenotype, and from our report of clinical samples, Notch up regulation was associated with poor outcome even after initial therapy such as surgery [57]. Both mouse models and human clinical samples show that notch promotion results in poor survival prognoses; thus, it would be a useful biomarker for aggressive types of liver cancer. Experimentally, GSIs are useful for tumor suppression and prolong survival in mouse liver tumor models [100-102]. GSIs have already been investigated in clinical trials for Alzheimer's disease; however, the trials were terminated because of gastrointestinal toxicity [103,104]. Several types of GSIs are in ongoing investigations and some exhibit less toxicity, therefore they may be useful as anticancer therapies [105]. The pharmacological characteristics show that there are some differences in the catalytic positions of gamma secretase at the transmembrane region and several types of GSIs have been introduced [106-108]. One GSI shows less gastrointestinal toxicity and is in ongoing clinical trials [103,109]. Besides reports of GSIs treatments for liver cancer, there are some Notch targeting therapies using other clinically relevant drugs. The combination therapy reports the effects of IL-17 antibody Secukinumab and with IL-35 that shows blockade of Notch signaling pathway [110]. Akt inhibitor effect for suppressing hepatoma cells proliferation by modulating PI3-K/Akt and Notch pathway is also reported [111]. Thymoquinone is reported Notch inhibiting effect with cell cycle suppression that related with NICD expression [112]. Moreover, this drug may be useful in combination with other anticancer therapies. Anticancer therapies for liver cancer do not always need to be systemic, since localized therapy such as radio frequency ablation (RFA) or transcatheter arterial chemoembolization (TACE) may be useful. It may be more effective to administer GSIs locally along with these therapies to reduce the adverse effects associated with GSIs.


Notch Signaling and Liver Immunity

Burghardt, et al. reported that immune regulation in the liver is associated with Notch activation in T cells, especially in the regeneration of livers of Con-A treated mice via an induced regulatory phenotype in naïve CD4+T cells [113,114]. These T regulatory cells release IL-10 and produce IFN-γ associated with the activation of Notch signaling [115]. Con A-pretreated mice show increased Jagged1 expression with high receptor density of Notch1 in CD4+T cells. Th1 cell Notch up regulation, particularly Jagged1 production, indicates liver inflammation, which is associated with liver regeneration after Th-1-mediated hepatitis. Another report has shown that liver sinusoidal endothelial cells (LSECs) induce immunosuppressive IL-10-producing Th1 cells via Notch signaling [115]. The group studied the capacity of LSECs in the regulation of T-cell induced liver regeneration. They found that DLL and JAG family Notch ligands induce activation of downstream HES-1 and deltex-1 in Th1 cells and this is associated with liver inflammation. Other reports have hypothesized that DLL4-Notch signaling is only associated with inflammatory responses, and these immune responses appear in adipose tissue, arteries, vein grafts, and the liver via macrophage activation associated with IL-1b, IL-6, CCL2/MCP-1, iNOS, NF-kB, DLL4, and MMP-9 and MMP-13 [52,116,117]. These inflammation processes related with Notch signaling are very close with not only liver regeneration after acute or chronic liver injury but also key immune molecules for cancer therapy for malignancies and immunity against infections [118].


Notch Signaling is Closely Associated with Liver Diseases and Useful Key Molecules for Liver Cancer Therapy

Reports show that liver diseases are associated with abnormal Notch signal transduction because disease arises from abnormalities in the signaling between adjacent cells-whether the cells are of the same type or not-and Notch signaling is closely associated with the development of many types of cells, including cancer cells and immune cells. The mechanism applies to liver diseases related to infection with hepatitis viruses, including HBV and HCV. Such viruses contribute to advanced liver disease via Notch signaling abnormalities and, based on clinical data, exhibit aggressive cancer phenotypes and poor prognoses. HBV-x contributes to Notch activation and promotes liver carcinogenesis, and HCV core protein is also associated with gamma secretase catalysis at the transmembrane region. These mechanisms are associated with cell-to-cell contact, and closely linked to signal transduction. Liver immune function may be associated with Notch signaling in cases of regeneration after liver injury. Anticancer therapies related with Notch signaling for liver cancer are ongoing in various basic and clinical studies, and from many recent reports indicate that modulating Notch signaling is useful therapies to the extent of targeting cancer stem cells, highly malignant and short prognosis types of cancer cells and holding immune modulating effect. These characteristics will result in improving prognosis in combination with existing therapies.


Conclusion

Notch signaling abnormalities are present in various liver diseases and affected by changes in the tissue microenvironment in the liver. These changes originate from hepatocytes and non-hepatocyte cells, including lymphoid, endothelial, stellate, and cholangiocyte cells. Notch inhibition related anti-cancer therapy is useful for hepato-biliary malignancies and may be more effective in combination with existing anticancer drugs.


References
  1. SKopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137: 216-233.

  2. Morgan TH, Bridges CB (1919) The Inheritance of a Fluctuating Character. J Gen Physiol 1: 639-643.

  3. Poulson DF (1937) Chromosomal Deficiencies and the Embryonic Development of Drosophila Melanogaster. Proc Natl Acad Sci U S A 23: 133-137.

  4. Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S (1985) Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 43: 567-581.

  5. Kidd S, Lockett TJ, Young MW (1983) The Notch locus of Drosophila melanogaster. Cell 34: 421-433.

  6. Yochem J, Greenwald I (1989) glp-1 and lin-12, genes implicated in distinct cell-cell interactions in C. elegans, encode similar transmembrane proteins. Cell 58: 553-563.

  7. Austin J, Kimble J (1989) Transcript analysis of glp-1 and lin-12, homologous genes required for cell interactions during development of C. elegans. Cell 58: 565-571.

  8. Levitan D, Greenwald I (1995) Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 377: 351-354.

  9. Kopan R, Nye JS, Weintraub H (1994) The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. Development 120: 2385-2396.

  10. Kageyama R, Niwa Y, Shimojo H, Kobayashi T, Ohtsuka T (2010) Ultradian oscillations in Notch signaling regulate dynamic biological events. Curr Top Dev Biol 92: 311-331.

  11. Kobayashi T, Mizuno H, Imayoshi I, Furusawa C, Shirahige K, et al. (2009) The cyclic gene Hes1 contributes to diverse differentiation responses of embryonic stem cells. Genes Dev 23: 1870-1875.

  12. Fior R, Henrique D (2009) "Notch-Off": a perspective on the termination of Notch signalling. Int J Dev Biol 53: 1379-1384.

  13. Takeuchi H, Haltiwanger RS (2014) Significance of glycosylation in Notch signaling. Biochem Biophys Res Commun 453: 235-242.

  14. Taylor P, Takeuchi H, Sheppard D, Chillakuri C, Lea SM, et al. (2014) Fringe-mediated extension of O-linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands. Proc Natl Acad Sci U S A 111: 7290-7295.

  15. Luca VC, Jude KM, Pierce NW, Nachury MV, Fischer S, et al. (2015) Structural biology. Structural basis for Notch1 engagement of Delta-like 4. Science 347: 847-853.

  16. Yamamoto S, Charng WL, Rana NA, Kakuda S, Jaiswal M, et al. (2012) A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands. Science 338: 1229-1232.

  17. Gordon WR, Zimmerman B, He L, Miles LJ, Huang J, et al. (2015) Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch. Dev Cell 33: 729-736.

  18. Palmer WH, Deng WM (2015) Ligand-Independent Mechanisms of Notch Activity. Trends Cell Biol 25: 697-707.

  19. Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7: 678-689.

  20. Haines N, Irvine KD (2003) Glycosylation regulates Notch signalling. Nat Rev Mol Cell Biol 4: 786-797.

  21. Doe CQ, Goodman CS (1985) Early events in insect neurogenesis. II. The role of cell interactions and cell lineage in the determination of neuronal precursor cells. Dev Biol 111: 206-219.

  22. Louvi A, Artavanis-Tsakonas S (2012) Notch and disease: a growing field. Semin Cell Dev Biol 23: 473-480.

  23. Shimojo H, Ohtsuka T, Kageyama R (2008) Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58: 52-64.

  24. Imayoshi I, Isomura A, Harima Y, Kawaguchi K, Kori H, et al. (2013) Oscillatory control of factors determining multipotency and fate in mouse neural progenitors. Science 342: 1203-1208.

  25. Li L, Krantz ID, Deng Y, Genin A, Banta AB, et al. (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16: 243-251.

  26. Oda T, Elkahloun AG, Meltzer PS, Okajima K, Sugiyama K, et al. (2000) Identification of a larger than 3 Mb deletion including JAG1 in an Alagille syndrome patient with a translocation t(3;20)(q13.3;p12.2). Hum Mutat 16: 92.

  27. Oda T, Elkahloun AG, Meltzer PS, Chandrasekharappa SC (1997) Identification and cloning of the human homolog (JAG1) of the rat Jagged1 gene from the Alagille syndrome critical region at 20p12. Genomics 43: 376-379.

  28. Alagille D, Gautier M, Habib EC, Dommergues JP (1969) Pre- and postoperative hepatic biopsy data in prolonged cholestasis in infants. Study of 128 cases. Arch Fr Pediatr 26: 283-296.

  29. Alagille D, Borde J, Habib EC, Dommergues JP (1969) Biliary surgery of prolonged cholestasis in young infants. Surgical data in 128 cases. Arch Fr Pediatr 26: 37-49.

  30. Alagille D, Borde J, Habib EC, Thomassin N (1969) Surgical attempts in atresia of the intrahepatic bile ducts with permeable extrahepatic bile duct. Study of 14 cases in children. Arch Fr Pediatr 26: 51-71.

  31. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, et al. (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16: 235-242.

  32. Artavanis-Tsakonas S (1997) Alagille syndrome--a notch up for the Notch receptor. Nat Genet 16: 212-213.

  33. Krantz ID, Rand EB, Genin A, Hunt P, Jones M, et al. (1997) Deletions of 20p12 in Alagille syndrome: frequency and molecular characterization. Am J Med Genet 70: 80-86.

  34. McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, et al. (2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 79: 169-173.

  35. Berniczei-Royko A, Chalas R, Mitura I, Nagy K, Prussak E (2014) Medical and dental management of Alagille syndrome: a review. Med Sci Monit 20: 476-480.

  36. Ma YL, Song YZ (2014) Advances in the diagnosis and treatment of Alagille syndrome. Zhongguo Dang Dai Er Ke Za Zhi 16: 1188-1192.

  37. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, et al. (2005) Mutations in NOTCH1 cause aortic valve disease. Nature 437: 270-274.

  38. Li Y, Takeshita K, Liu PY, Satoh M, Oyama N, et al. (2009) Smooth muscle Notch1 mediates neointimal formation after vascular injury. Circulation 119: 2686-2692.

  39. Shimizu T, Tanaka T, Iso T, Doi H, Sato H, et al. (2009) Notch signaling induces osteogenic differentiation and mineralization of vascular smooth muscle cells: role of Msx2 gene induction via Notch-RBP-Jk signaling. Arterioscler Thromb Vasc Biol 29: 1104-1111.

  40. Kola S, Koneti NR, Golla JP, Akka J, Gundimeda SD, et al. (2011) Mutational analysis of JAG1 gene in non-syndromic tetralogy of Fallot children. Clin Chim Acta 412: 2232-2236.

  41. Bauer RC, Laney AO, Smith R, Gerfen J, Morrissette JJ, et al. (2010) Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis. Hum Mutat 31: 594-601.

  42. Monet-Leprêtre M, Bardot B, Lemaire B, Domenga V, Godin O, et al. (2009) Distinct phenotypic and functional features of CADASIL mutations in the Notch3 ligand binding domain. Brain 132: 1601-1612.

  43. Tikka S, Mykkänen K, Ruchoux MM, Bergholm R, Junna M, et al. (2009) Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain 132: 933-939.

  44. Joutel A, Vahedi K, Corpechot C, Troesch A, Chabriat H, et al. (1997) Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 350: 1511-1515.

  45. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, et al. (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383: 707-710.

  46. Doi H, Iso T, Shiba Y, Sato H, Yamazaki M, et al. (2009) Notch signaling regulates the differentiation of bone marrow-derived cells into smooth muscle-like cells during arterial lesion formation. Biochem Biophys Res Commun 381: 654-659.

  47. Liu ZJ, Tan Y, Beecham GW, Seo DM, Tian R, et al. (2012) Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis. Atherosclerosis 225: 296-303.

  48. Fung E, Tang SM, Canner JP, Morishige K, Arboleda-Velasquez JF, et al. (2007) Delta-like 4 induces notch signaling in macrophages: implications for inflammation. Circulation 115: 2948-2956.

  49. Radtke F (2012) From the cradle to the work place: pleitropic roles of Notch in immunity. (Preface). Curr Top Microbiol Immunol 360.

  50. Radtke F, Fasnacht N, Macdonald HR (2010) Notch signaling in the immune system. Immunity 32: 14-27.

  51. Nakano T, Fukuda D, Koga J, Aikawa M (2016) Delta-Like Ligand 4-Notch Signaling in Macrophage Activation. Arterioscler Thromb Vasc Biol 36: 2038-2047.

  52. Fukuda D, Aikawa E, Swirski FK, Novobrantseva TI, Kotelianski V, et al. (2012) Notch ligand delta-like 4 blockade attenuates atherosclerosis and metabolic disorders. Proc Natl Acad Sci U S A 109: E1868-E1877.

  53. Aikawa M, Libby P (2004) The vulnerable atherosclerotic plaque: pathogenesis and therapeutic approach. Cardiovasc Pathol 13: 125-138.

  54. Sekiya S, Suzuki A (2012) Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J Clin Invest 122: 3914-3918.

  55. Gao J, Chen Y, Wu KC, Liu J, Zhao YQ, et al. (2010) RUNX3 directly interacts with intracellular domain of Notch1 and suppresses Notch signaling in hepatocellular carcinoma cells. Exp Cell Res 316: 149-157.

  56. Nishina S, Shiraha H, Nakanishi Y, Tanaka S, Matsubara M, et al. (2011) Restored expression of the tumor suppressor gene RUNX3 reduces cancer stem cells in hepatocellular carcinoma by suppressing Jagged1-Notch signaling. Oncol Rep 26: 523-531.

  57. Kawaguchi K, Honda M, Yamashita T, Okada H, Shirasaki T, et al. (2016) Jagged1 DNA Copy Number Variation Is Associated with Poor Outcome in Liver Cancer. Am J Pathol 186: 2055-2067.

  58. Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, et al. (2014) Hippo pathway activity influences liver cell fate. Cell 157: 1324-1338.

  59. Tschaharganeh DF, Chen X, Latzko P, Malz M, Gaida MM, et al. (2013) Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology 144: 1530-1542.

  60. Kim W, Khan SK, Gvozdenovic-Jeremic J, Kim Y, Dahlman J, et al. (2017) Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis. J Clin Invest 127: 137-152.

  61. Yang SL, Ren QG, Zhang T, Pan X, Wen L, et al. (2016) Hepatitis B virus X protein and hypoxia-inducible factor-1a stimulate Notch gene expression in liver cancer cells. Oncol Rep 37: 348-356.

  62. Trehanpati N, Shrivastav S, Shivakumar B, Khosla R, Bhardwaj S, et al. (2012) Analysis of Notch and TGF-ß Signaling Expression in Different Stages of Disease Progression During Hepatitis B Virus Infection. Clin Transl Gastroenterol 3: e23.

  63. Gao J, Xiong Y, Wang Y, Wang Y, Zheng G, et al. (2016) Hepatitis B virus X protein activates Notch signaling by its effects on Notch1 and Notch4 in human hepatocellular carcinoma. Int J Oncol 48: 329-337.

  64. Wang F, Zhou H, Xia X, Sun Q, Wang Y, et al. (2010) Activated Notch signaling is required for hepatitis B virus X protein to promote proliferation and survival of human hepatic cells. Cancer Lett 298: 64-73.

  65. Gao J, Chen C, Hong L, Wang J, Du Y, et al. (2007) Expression of Jagged1 and its association with hepatitis B virus X protein in hepatocellular carcinoma. Biochem Biophys Res Commun 356: 341-347.

  66. Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B (2002) Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296: 2215-2218.

  67. Weihofen A, Lemberg MK, Friedmann E, Rueeger H, Schmitz A, et al. (2003) Targeting presenilin-type aspartic protease signal peptide peptidase with gamma-secretase inhibitors. J Biol Chem 278: 16528-16533.

  68. Kitade M, Factor VM, Andersen JB, Tomokuni A, Kaji K, et al. (2013) Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling. Genes Dev 27: 1706-1717.

  69. Annani-Akollor ME, Wang S, Fan J, Liu L, Padhiar AA, et al. (2014) Downregulated protein O-fucosyl transferase 1 (Pofut1) expression exerts antiproliferative and antiadhesive effects on hepatocytes by inhibiting Notch signalling. Biomed Pharmacother 68: 785-790.

  70. Thakurdas SM, Lopez MF, Kakuda S, Fernandez-Valdivia R, Zarrin-Khameh N, et al. (2016) Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi). Hepatology 63: 550-565.

  71. Zheng S, Zhang P, Chen Y, Zheng L, Weng Z (2016) Inhibition of Notch Signaling Attenuates Schistosomiasis Hepatic Fibrosis via Blocking Macrophage M2 Polarization. PLoS One 11: e0166808.

  72. Bansal R, van Baarlen J, Storm G, Prakash J (2015) The interplay of the Notch signaling in hepatic stellate cells and macrophages determines the fate of liver fibrogenesis. Sci Rep 5: 18272.

  73. Xu J, Chi F, Tsukamoto H (2015) Notch signaling and M1 macrophage activation in obesity-alcohol synergism. Clin Res Hepatol Gastroenterol 1: S24-S28.

  74. Mushref M, Shah VH (2015) Getting a NOTCH-up on Macrophage Activation in Alcoholic Liver Disease. Gastroenterology 149: 1979-1980.

  75. Iida H, Honda M, Kawai HF, Yamashita T, Shirota Y, et al. (2005) Ephrin-A1 expression contributes to the malignant characteristics of {alpha}-fetoprotein producing hepatocellular carcinoma. Gut 54: 843-851.

  76. Iwamoto H, Zhang Y, Seki T, Yang Y, Nakamura M, et al. (2015) PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors. Sci Adv 1: e1400244.

  77. Zeng J, Jing Y, Shi R, Pan X, Lai F, et al. (2016) Autophagy regulates biliary differentiation of hepatic progenitor cells through Notch1 signaling pathway. Cell Cycle 15: 1602-1610.

  78. Wang M, Xue L, Cao Q, Lin Y, Ding Y, et al. (2009) Expression of Notch1, Jagged1 and beta-catenin and their clinicopathological significance in hepatocellular carcinoma. Neoplasma 56: 533-541.

  79. Hayashi Y, Osanai M, Lee GH (2015) NOTCH2 signaling confers immature morphology and aggressiveness in human hepatocellular carcinoma cells. Oncol Rep 34: 1650-1658.

  80. Falix FA, Weeda VB, Labruyere WT, Poncy A, de Waart DR, et al. (2014) Hepatic Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning. Dev Biol 396: 201-213.

  81. Dill MT, Tornillo L, Fritzius T, Terracciano L, Semela D, et al. (2013) Constitutive Notch2 signaling induces hepatic tumors in mice. Hepatology 57: 1607-1619

  82. Litten JB, Chen TT, Schultz R, Herman K, Comstock J, et al. (2011) Activated NOTCH2 is overexpressed in hepatoblastomas: an immunohistochemical study. Pediatr Dev Pathol 14: 378-383.

  83. Guest RV, Boulter L, Dwyer BJ, Kendall TJ, Man TY, et al. (2016) Notch3 drives development and progression of cholangiocarcinoma. Proc Natl Acad Sci U S A 113: 12250-12255.

  84. Zheng SP, Chen YX, Guo JL, Qi D, Zheng SJ, et al. (2013) Recombinant adeno-associated virus-mediated transfer of shRNA against Notch3 ameliorates hepatic fibrosis in rats. Exp Biol Med (Maywood) 238: 600-609

  85. Jie LU, Yujing Xia, Kan Chen, Yuanyuan Zheng, Jianrong Wang, et al. (2016) Oncogenic role of the Notch pathway in primary liver cancer. Oncol Lett 12: 3-10.

  86. Carlson TR, Yan Y, Wu X, Lam MT, Tang GL, et al. (2005) Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci U S A 102: 9884-9889.

  87. Ortica S, Tarantino N, Aulner N, Israël A (2014) The 4 Notch receptors play distinct and antagonistic roles in the proliferation and hepatocytic differentiation of liver progenitors. FASEB J 28: 603-614.

  88. Ahn S, Hyeon J, Park CK (2013) Notch1 and Notch4 are markers for poor prognosis of hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 12: 286-294.

  89. Penton AL, Leonard LD, Spinner NB (2012) Notch signaling in human development and disease. Semin Cell Dev Biol 23: 450-457.

  90. Kongkavitoon P, Tangkijvanich P, Hirankarn N, Palaga T (2016) Hepatitis B Virus HBx Activates Notch Signaling via Delta-Like 4/Notch1 in Hepatocellular Carcinoma. PLoS One 11: e0146696.

  91. Fukuda D, Aikawa M (2013) Expanding role of delta-like 4 mediated notch signaling in cardiovascular and metabolic diseases. Circ J 77: 2462-2468.

  92. Wei X, Wang JP, Hao CQ, Yang XF, Wang LX, et al. (2016) Notch Signaling Contributes to Liver Inflammation by Regulation of Interleukin-22-Producing Cells in Hepatitis B Virus Infection. Front Cell Infect Microbiol 6: 132.

  93. Köchert K, Ullrich K, Kreher S, Aster JC, Kitagawa M, et al. (2011) High-level expression of Mastermind-like 2 contributes to aberrant activation of the NOTCH signaling pathway in human lymphomas. Oncogene 30: 1831-1840.

  94. Nemoto N, Suzukawa K, Shimizu S, Shinagawa A, Takei N, et al. (2007) Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23). Genes Chromosomes Cancer 46: 813-819.

  95. Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P,et al. (2006) A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12: 410-416.

  96. Augusto Villanueva, Clara Alsinet, Kilangsungla Yanger, Yujin Hoshida, Yiwei Zong, et al. (2012) Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology 143: 1660-1669.

  97. Jeliazkova P, Jörs S, Lee M, Zimber-Strobl U, Ferrer J, et al. (2013) Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1. Hepatology 57: 2469-2479.

  98. Liu C, Liu L, Chen X, Cheng J, Zhang H, et al. (2016) Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma. Hepatology 64: 117-129.

  99. Rong Zhu, Jing Yang, Ling Xu, Weiqi Dai, Fan Wa, et al. (2014) Diagnostic Performance of Des-?-carboxy Prothrombin for Hepatocellular Carcinoma: A Meta-Analysis. Gastroenterol Res Pract.

  100. Gao J, Dong Y, Zhang B, Xiong Y, Xu W, et al. (2012) Notch1 activation contributes to tumor cell growth and proliferation in human hepatocellular carcinoma HepG2 and SMMC7721 cells. Int J Oncol 41: 1773-1781.

  101. Shen Y, Lv D, Wang J, Yin Y, Miao F, et al. (2012) GSI-I has a better effect in inhibiting hepatocellular carcinoma cell growth than GSI-IX, GSI-X, or GSI-XXI. Anticancer Drugs 23: 683-690.

  102. Suwanjunee S, Wongchana W, Palaga T (2008) Inhibition of gamma-secretase affects proliferation of leukemia and hepatoma cell lines through Notch signaling. Anticancer Drugs 19: 477-486.

  103. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, et al. (2013) A phase 3 trial of semagacestat for treatment of Alzheimer's disease. N Engl J Med 369: 341-350.

  104. He G, Luo W, Li P, Remmers C, Netzer WJ, et al. (2010) Gamma-secretase activating protein is a therapeutic target for Alzheimer's disease. Nature 467: 95-98.

  105. Nakano-Ito K, Fujikawa Y, Hihara T, Shinjo H, Kotani S, et al. (2014) E2012-induced cataract and its predictive biomarkers. Toxicol Sci 137: 249-258.

  106. Morohashi Y, Kan T, Tominari Y, Fuwa H, Okamura Y, et al. (2006) C-terminal fragment of presenilin is the molecular target of a dipeptidic gamma-secretase-specific inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester). J Biol Chem 281: 14670-14676.

  107. Ogura T, Mio K, Hayashi I, Miyashita H, Fukuda R, et al. (2006) Three-dimensional structure of the gamma-secretase complex. Biochem Biophys Res Commun 343: 525-534.

  108. Sato C, Morohashi Y, Tomita T, Iwatsubo T (2006) Structure of the catalytic pore of gamma-secretase probed by the accessibility of substituted cysteines. J Neurosci 26: 12081-12088.

  109. Shan W, Balog A, Quesnelle C, Gill P, Han WC, et al. (2015) BMS-871: a novel orally active pan-Notch inhibitor as an anticancer agent. Bioorg Med Chem Lett 25: 1905-1909.

  110. Li HCh, Zhang YX, Liu Y, Wang QSh (2016) Effect of IL-17 monoclonal antibody Secukinumab combined with IL-35 blockade of Notch signaling pathway on the invasive capability of hepatoma cells. Genet Mol Res 15.

  111. Sokolowski KM, Balamurugan M, Kunnimalaiyaan S, Wilson J, Gamblin TC, et al. (2016) Role of Akt inhibition on Notch1 expression in hepatocellular carcinoma: potential role for dual targeted therapy. Am J Surg 211: 755-760.

  112. Ke X, Zhao Y, Lu X, Wang Z, Liu Y, et al. (2015) TQ inhibits hepatocellular carcinoma growth in vitro and in vivo via repression of Notch signaling. Oncotarget 6: 32610-32621.

  113. Burghardt S, Erhardt A, Claass B, Huber S, Adler G, et al. (2013) Hepatocytes contribute to immune regulation in the liver by activation of the Notch signaling pathway in T cells. J Immunol 191: 5574-5582.

  114. Burghardt S, Claass B, Erhardt A, Karimi K, Tiegs G (2014) Hepatocytes induce Foxp3⁺ regulatory T cells by Notch signaling. J Leukoc Biol 96: 571-577.

  115. Neumann K, Rudolph C, Neumann C, Janke M, Amsen D, et al. (2015) Liver sinusoidal endothelial cells induce immunosuppressive IL-10-producing Th1 cells via the Notch pathway. Eur J Immunol 45: 2008-2016.

  116. Chartoumpekis DV, Palliyaguru DL, Wakabayashi N, Khoo NK, Schoiswohl G, et al. (2015) Notch intracellular domain overexpression in adipocytes confers lipodystrophy in mice. Mol Metab 4: 543-550.

  117. Sparling DP, Yu J, Kim K, Zhu C, Brachs S, et al. (2016) Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity. Mol Metab 5: 113-121.

  118. Bachanova V, McCullar V, Lenvik T, Wangen R, Peterson KA, et al. (2009) Activated notch supports development of cytokine producing NK cells which are hyporesponsive and fail to acquire NK cell effector functions. Biol Blood Marrow Transplant 15: 183-194.

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