Abstract
Interactions between liver cells are closely regulated by Notch signaling. Notch signaling has been reported clinically related to bile duct hypogenesis in Alagille syndrome, which is caused by mutations in the Jagged1 gene. Notch activation and hepatocarcinogenesis are closely associated since cancer signaling is affected by the development of liver cells and cancer stem cells. Gene expression and genomic analysis using a microarray revealed that abnormalities in Notch-related genes were associated with the aggressiveness of liver cancer. This pattern was also accompanied with α-fetoprotein- and EpCAM-expressing phenotypes in vitro, in vivo, and in clinical tissues. Hepatitis B or C virus chronic infection or alcohol- or steatosis-related liver fibrosis induces liver cancer. Previous reports demonstrated that HBx, a hepatitis B virus protein, was associated with Jagged1 expression. We found that the Jagged1 and Notch1 signaling pathways were closely associated with the transcription of covalently closed circular hepatitis B virus DNA, which regulated cAMP response element-binding protein, thereby affecting Notch1 regulation by the E3 ubiquitin ligase ITCH. This viral pathogenesis in hepatocytes induces liver cancer. In conclusion, Notch signaling exerts various actions and is a clinical signature associated with hepatocarcinogenesis and liver context-related developmental function.
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Adams JM, Jafar-Nejad H (2019) The roles of Notch signaling in liver development and disease. Biomol Ther 9(10). https://doi.org/10.3390/biom9100608
Ahn S, Hyeon J, Park CK (2013) Notch1 and Notch4 are markers for poor prognosis of hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 12(3):286–294. https://doi.org/10.1016/s1499-3872(13)60046-6
Annani-Akollor ME, Wang S, Fan J, Liu L, Padhiar AA, Zhang J (2014) Downregulated protein O-fucosyl transferase 1 (Pofut1) expression exerts antiproliferative and antiadhesive effects on hepatocytes by inhibiting Notch signalling. Biomed Pharmacother 68(6):785–790. https://doi.org/10.1016/j.biopha.2014.07.005
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. https://doi.org/10.1038/srep18272
Carlson TR, Yan Y, Wu X, Lam MT, Tang GL, Beverly LJ, Messina LM, Capobianco AJ, Werb Z, Wang R (2005) Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci U S A 102(28):9884–9889. https://doi.org/10.1073/pnas.0504391102
Dill MT, Tornillo L, Fritzius T, Terracciano L, Semela D, Bettler B, Heim MH, Tchorz JS (2013) Constitutive Notch2 signaling induces hepatic tumors in mice. Hepatology 57(4):1607–1619. https://doi.org/10.1002/hep.26165
Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, Aisen PS, Alzheimer’s Disease Cooperative Study Steering C, Siemers E, Sethuraman G, Mohs R, Semagacestat Study G (2013) A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 369(4):341–350. https://doi.org/10.1056/NEJMoa1210951
Duan JL, Ruan B, Yan XC, Liang L, Song P, Yang ZY, Liu Y, Dou KF, Han H, Wang L (2018) Endothelial Notch activation reshapes the angiocrine of sinusoidal endothelia to aggravate liver fibrosis and blunt regeneration in mice. Hepatology 68(2):677–690. https://doi.org/10.1002/hep.29834
Falix FA, Weeda VB, Labruyere WT, Poncy A, de Waart DR, Hakvoort TB, Lemaigre F, Gaemers IC, Aronson DC, Lamers WH (2014) Hepatic Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning. Dev Biol 396(2):201–213. https://doi.org/10.1016/j.ydbio.2014.10.002
Fukuda D, Aikawa M (2013) Expanding role of delta-like 4 mediated notch signaling in cardiovascular and metabolic diseases. Circ J 77(10):2462–2468. https://doi.org/10.1253/circj.cj-13-0873
Fukuda D, Aikawa E, Swirski FK, Novobrantseva TI, Kotelianski V, Gorgun CZ, Chudnovskiy A, Yamazaki H, Croce K, Weissleder R, Aster JC, Hotamisligil GS, Yagita H, Aikawa M (2012) Notch ligand delta-like 4 blockade attenuates atherosclerosis and metabolic disorders. Proc Natl Acad Sci U S A 109(27):E1868–E1877. https://doi.org/10.1073/pnas.1116889109
Gao J, Chen C, Hong L, Wang J, Du Y, Song J, Shao X, Zhang J, Han H, Liu J, Fan D (2007) Expression of Jagged1 and its association with hepatitis B virus X protein in hepatocellular carcinoma. Biochem Biophys Res Commun 356(2):341–347. https://doi.org/10.1016/j.bbrc.2007.02.130
Gao J, Chen Y, Wu KC, Liu J, Zhao YQ, Pan YL, Du R, Zheng GR, Xiong YM, Xu HL, Fan DM (2010) RUNX3 directly interacts with intracellular domain of Notch1 and suppresses Notch signaling in hepatocellular carcinoma cells. Exp Cell Res 316(2):149–157. https://doi.org/10.1016/j.yexcr.2009.09.025
Gao J, Dong Y, Zhang B, Xiong Y, Xu W, Cheng Y, Dai M, Yu Z, Xu H, Zheng G (2012) Notch1 activation contributes to tumor cell growth and proliferation in human hepatocellular carcinoma HepG2 and SMMC7721 cells. Int J Oncol 41(5):1773–1781. https://doi.org/10.3892/ijo.2012.1606
Gao J, Xiong Y, Wang Y, Wang Y, Zheng G, Xu H (2016) Hepatitis B virus X protein activates Notch signaling by its effects on Notch1 and Notch4 in human hepatocellular carcinoma. Int J Oncol 48(1):329–337. https://doi.org/10.3892/ijo.2015.3221
Geisler F, Strazzabosco M (2015) Emerging roles of Notch signaling in liver disease. Hepatology 61(1):382–392. https://doi.org/10.1002/hep.27268
Geisler F, Nagl F, Mazur PK, Lee M, Zimber-Strobl U, Strobl LJ, Radtke F, Schmid RM, Siveke JT (2008) Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology 48(2):607–616. https://doi.org/10.1002/hep.22381
Guest RV, Boulter L, Dwyer BJ, Kendall TJ, Man TY, Minnis-Lyons SE, Lu WY, Robson AJ, Gonzalez SF, Raven A, Wojtacha D, Morton JP, Komuta M, Roskams T, Wigmore SJ, Sansom OJ, Forbes SJ (2016) Notch3 drives development and progression of cholangiocarcinoma. Proc Natl Acad Sci U S A 113(43):12250–12255. https://doi.org/10.1073/pnas.1600067113
Hayashi Y, Osanai M, Lee GH (2015) NOTCH2 signaling confers immature morphology and aggressiveness in human hepatocellular carcinoma cells. Oncol Rep 34(4):1650–1658. https://doi.org/10.3892/or.2015.4171
He G, Luo W, Li P, Remmers C, Netzer WJ, Hendrick J, Bettayeb K, Flajolet M, Gorelick F, Wennogle LP, Greengard P (2010) Gamma-secretase activating protein is a therapeutic target for Alzheimer’s disease. Nature 467(7311):95–98. https://doi.org/10.1038/nature09325
Iwamoto H, Zhang Y, Seki T, Yang Y, Nakamura M, Wang J, Yang X, Torimura T, Cao Y (2015) PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors. Sci Adv 1(3):e1400244. https://doi.org/10.1126/sciadv.1400244
Jeliazkova P, Jors S, Lee M, Zimber-Strobl U, Ferrer J, Schmid RM, Siveke JT, Geisler F (2013) Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1. Hepatology 57(6):2469–2479. https://doi.org/10.1002/hep.26254
Kawaguchi K, Honda M, Yamashita T, Okada H, Shirasaki T, Nishikawa M, Nio K, Arai K, Sakai Y, Yamashita T, Mizukoshi E, Kaneko S (2016) Jagged1 DNA copy number variation is associated with poor outcome in liver cancer. Am J Pathol 186(8):2055–2067. https://doi.org/10.1016/j.ajpath.2016.04.011
Ke X, Zhao Y, Lu X, Wang Z, Liu Y, Ren M, Lu G, Zhang D, Sun Z, Xu Z, Song JH, Cheng Y, Meltzer SJ, He S (2015) TQ inhibits hepatocellular carcinoma growth in vitro and in vivo via repression of Notch signaling. Oncotarget 6(32):32610–32621. https://doi.org/10.18632/oncotarget.5362
Kim W, Khan SK, Gvozdenovic-Jeremic J, Kim Y, Dahlman J, Kim H, Park O, Ishitani T, Jho EH, Gao B, Yang Y (2017) Hippo signaling interactions with Wnt/beta-catenin and Notch signaling repress liver tumorigenesis. J Clin Invest 127(1):137–152. https://doi.org/10.1172/JCI88486
Kitade M, Kaji K, Nishimura N, Seki K, Nakanishi K, Tsuji Y, Sato S, Saikawa S, Takaya H, Kawaratani H, Namisaki T, Moriya K, Mitoro A, Yoshiji H (2019) Blocking development of liver fibrosis augments hepatic progenitor cell-derived liver regeneration in a mouse chronic liver injury model. Hepatol Res 49(9):1034–1045. https://doi.org/10.1111/hepr.13351
Ko S, Russell JO, Tian J, Gao C, Kobayashi M, Feng R, Yuan X, Shao C, Ding H, Poddar M, Singh S, Locker J, Weng HL, Monga SP, Shin D (2019) Hdac1 regulates differentiation of bipotent liver progenitor cells during regeneration via Sox9b and Cdk8. Gastroenterology 156(1):187-202 e114. https://doi.org/10.1053/j.gastro.2018.09.039
Kochert K, Ullrich K, Kreher S, Aster JC, Kitagawa M, Johrens K, Anagnostopoulos I, Jundt F, Lamprecht B, Zimber-Strobl U, Stein H, Janz M, Dorken B, Mathas S (2011) High-level expression of Mastermind-like 2 contributes to aberrant activation of the NOTCH signaling pathway in human lymphomas. Oncogene 30(15):1831–1840. https://doi.org/10.1038/onc.2010.544
Koike H, Iwasawa K, Ouchi R, Maezawa M, Giesbrecht K, Saiki N, Ferguson A, Kimura M, Thompson WL, Wells JM, Zorn AM, Takebe T (2019) Modelling human hepato-biliary-pancreatic organogenesis from the foregut-midgut boundary. Nature 574(7776):112–116. https://doi.org/10.1038/s41586-019-1598-0
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(1):e0146696. https://doi.org/10.1371/journal.pone.0146696
Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, Mikaelyan A, Roberts LR, Demetris AJ, Sun Z, Nevens F, Roskams T, Thorgeirsson SS (2006) A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12(4):410–416. https://doi.org/10.1038/nm1377
Lee DH, Park JO, Kim TS, Kim SK, Kim TH, Kim MC, Park GS, Kim JH, Kuninaka S, Olson EN, Saya H, Kim SY, Lee H, Lim DS (2016) LATS-YAP/TAZ controls lineage specification by regulating TGFbeta signaling and Hnf4alpha expression during liver development. Nat Commun 7:11961. https://doi.org/10.1038/ncomms11961
Li H, Zhang YX, Liu Y, Wang Q (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(2). https://doi.org/10.4238/gmr.15028174
Litten JB, Chen TT, Schultz R, Herman K, Comstock J, Schiffman J, Tomlinson GE, Rakheja D (2011) Activated NOTCH2 is overexpressed in hepatoblastomas: an immunohistochemical study. Pediatr Dev Pathol 14(5):378–383. https://doi.org/10.2350/10-09-0900-OA.1
Liu C, Liu L, Chen X, Cheng J, Zhang H, Shen J, Shan J, Xu Y, Yang Z, Lai M, Qian C (2016) Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma. Hepatology 64(1):117–129. https://doi.org/10.1002/hep.28509
Liu C, Liu L, Chen X, Cheng J, Zhang H, Zhang C, Shan J, Shen J, Qian C (2018) LSD1 stimulates cancer-associated fibroblasts to drive Notch3-dependent self-renewal of liver cancer stem-like cells. Cancer Res 78(4):938–949. https://doi.org/10.1158/0008-5472.CAN-17-1236
Lu P, Bai XC, Ma D, Xie T, Yan C, Sun L, Yang G, Zhao Y, Zhou R, Scheres SHW, Shi Y (2014) Three-dimensional structure of human gamma-secretase. Nature 512(7513):166–170. https://doi.org/10.1038/nature13567
Lu J, Xia Y, Chen K, Zheng Y, Wang J, Lu W, Yin Q, Wang F, Zhou Y, Guo C (2016) Oncogenic role of the Notch pathway in primary liver cancer. Oncol Lett 12(1):3–10. https://doi.org/10.3892/ol.2016.4609
Luo J, Wang P, Wang R, Wang J, Liu M, Xiong S, Li Y, Cheng B (2016) The Notch pathway promotes the cancer stem cell characteristics of CD90+ cells in hepatocellular carcinoma. Oncotarget 7(8):9525–9537. https://doi.org/10.18632/oncotarget.6672
McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB (2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway. Am J Hum Genet 79(1):169–173. https://doi.org/10.1086/505332
Morohashi Y, Kan T, Tominari Y, Fuwa H, Okamura Y, Watanabe N, Sato C, Natsugari H, Fukuyama T, Iwatsubo T, Tomita T (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(21):14670–14676. https://doi.org/10.1074/jbc.M513012200
Nakano T, Fukuda D, Koga J, Aikawa M (2016) Delta-like ligand 4-Notch signaling in macrophage activation. Arterioscler Thromb Vasc Biol 36(10):2038–2047. https://doi.org/10.1161/ATVBAHA.116.306926
Nakano-Ito K, Fujikawa Y, Hihara T, Shinjo H, Kotani S, Suganuma A, Aoki T, Tsukidate K (2014) E2012-induced cataract and its predictive biomarkers. Toxicol Sci 137(1):249–258. https://doi.org/10.1093/toxsci/kft224
Nemoto N, Suzukawa K, Shimizu S, Shinagawa A, Takei N, Taki T, Hayashi Y, Kojima H, Kawakami Y, Nagasawa T (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(9):813–819. https://doi.org/10.1002/gcc.20467
Nishina S, Shiraha H, Nakanishi Y, Tanaka S, Matsubara M, Takaoka N, Uemura M, Horiguchi S, Kataoka J, Iwamuro M, Yagi T, Yamamoto K (2011) Restored expression of the tumor suppressor gene RUNX3 reduces cancer stem cells in hepatocellular carcinoma by suppressing Jagged1-Notch signaling. Oncol Rep 26(3):523–531. https://doi.org/10.3892/or.2011.1336
Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16(3):235–242. https://doi.org/10.1038/ng0797-235
Ortica S, Tarantino N, Aulner N, Israel A, Gupta-Rossi N (2014) The 4 Notch receptors play distinct and antagonistic roles in the proliferation and hepatocytic differentiation of liver progenitors. FASEB J 28(2):603–614. https://doi.org/10.1096/fj.13-235903
Penton AL, Leonard LD, Spinner NB (2012) Notch signaling in human development and disease. Semin Cell Dev Biol 23(4):450–457. https://doi.org/10.1016/j.semcdb.2012.01.010
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(46):12081–12088. https://doi.org/10.1523/JNEUROSCI.3614-06.2006
Sekiya S, Suzuki A (2012) Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J Clin Invest 122(11):3914–3918. https://doi.org/10.1172/JCI63065
Shan W, Balog A, Quesnelle C, Gill P, Han WC, Norris D, Mandal S, Thiruvenkadam R, Gona KB, Thiyagarajan K, Kandula S, McGlinchey K, Menard K, Wen ML, Rose A, White R, Guarino V, Shen DR, Cvijic ME, Ranasinghe A, Dai J, Zhang Y, Wu DR, Mathur A, Rampulla R, Trainor G, Hunt JT, Vite GD, Westhouse R, Lee FY, Gavai AV (2015) BMS-871: a novel orally active pan-Notch inhibitor as an anticancer agent. Bioorg Med Chem Lett 25(9):1905–1909. https://doi.org/10.1016/j.bmcl.2015.03.038
Shen Y, Lv D, Wang J, Yin Y, Miao F, Dou F, Zhang J (2012) GSI-I has a better effect in inhibiting hepatocellular carcinoma cell growth than GSI-IX, GSI-X, or GSI-XXI. Anti-Cancer Drugs 23(7):683–690. https://doi.org/10.1097/CAD.0b013e3283549a22
Sokolowski KM, Balamurugan M, Kunnimalaiyaan S, Wilson J, Gamblin TC, Kunnimalaiyaan M (2016) Role of Akt inhibition on Notch1 expression in hepatocellular carcinoma: potential role for dual targeted therapy. Am J Surg 211(4):755–760. https://doi.org/10.1016/j.amjsurg.2015.11.029
Sun L, Wang Y, Cen J, Ma X, Cui L, Qiu Z, Zhang Z, Li H, Yang RZ, Wang C, Chen X, Wang L, Ye Y, Zhang H, Pan G, Kang JS, Ji Y, Zheng YW, Zheng S, Hui L (2019) Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes. Nat Cell Biol 21(8):1015–1026. https://doi.org/10.1038/s41556-019-0359-5
Suwanjunee S, Wongchana W, Palaga T (2008) Inhibition of gamma-secretase affects proliferation of leukemia and hepatoma cell lines through Notch signaling. Anti-Cancer Drugs 19(5):477–486. https://doi.org/10.1097/CAD.0b013e3282fc6cdd
Thakurdas SM, Lopez MF, Kakuda S, Fernandez-Valdivia R, Zarrin-Khameh N, Haltiwanger RS, Jafar-Nejad H (2016) Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi). Hepatology 63(2):550–565. https://doi.org/10.1002/hep.28024
Trehanpati N, Shrivastav S, Shivakumar B, Khosla R, Bhardwaj S, Chaturvedi J, Sukriti KB, Bose S, Mani Tripathi D, Das T, Sakhuja P, Rastogi A, Bhihari C, Singh S, Gupta S, Kottilil S, Sarin SK (2012) Analysis of Notch and TGF-beta signaling expression in different stages of disease progression during hepatitis B virus infection. Clin Transl Gastroenterol 3:e23. https://doi.org/10.1038/ctg.2012.17
Tschaharganeh DF, Chen X, Latzko P, Malz M, Gaida MM, Felix K, Ladu S, Singer S, Pinna F, Gretz N, Sticht C, Tomasi ML, Delogu S, Evert M, Fan B, Ribback S, Jiang L, Brozzetti S, Bergmann F, Dombrowski F, Schirmacher P, Calvisi DF, Breuhahn K (2013) Yes-associated protein up-regulates Jagged-1 and activates the Notch pathway in human hepatocellular carcinoma. Gastroenterology 144(7):1530–1542 e1512. https://doi.org/10.1053/j.gastro.2013.02.009
Villanueva A, Alsinet C, Yanger K, Hoshida Y, Zong Y, Toffanin S, Rodriguez-Carunchio L, Sole M, Thung S, Stanger BZ, Llovet JM (2012) Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology 143(6):1660–1669 e1667. https://doi.org/10.1053/j.gastro.2012.09.002
Vyas D, Baptista PM, Brovold M, Moran E, Gaston B, Booth C, Samuel M, Atala A, Soker S (2018) Self-assembled liver organoids recapitulate hepatobiliary organogenesis in vitro. Hepatology 67(2):750–761. https://doi.org/10.1002/hep.29483
Wang M, Xue L, Cao Q, Lin Y, Ding Y, Yang P, Che L (2009) Expression of Notch1, Jagged1 and beta-catenin and their clinicopathological significance in hepatocellular carcinoma. Neoplasma 56(6):533–541. https://doi.org/10.4149/neo_2009_06_533
Wang F, Zhou H, Xia X, Sun Q, Wang Y, Cheng B (2010) Activated Notch signaling is required for hepatitis B virus X protein to promote proliferation and survival of human hepatic cells. Cancer Lett 298(1):64–73. https://doi.org/10.1016/j.canlet.2010.06.003
Wang R, Sun Q, Wang P, Liu M, Xiong S, Luo J, Huang H, Du Q, Geller DA, Cheng B (2016) Notch and Wnt/beta-catenin signaling pathway play important roles in activating liver cancer stem cells. Oncotarget 7(5):5754–5768. https://doi.org/10.18632/oncotarget.6805
Wang R, Li Y, Tsung A, Huang H, Du Q, Yang M, Deng M, Xiong S, Wang X, Zhang L, Geller DA, Cheng B, Billiar TR (2018) iNOS promotes CD24(+)CD133(+) liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway. Proc Natl Acad Sci U S A 115(43):E10127–E10136. https://doi.org/10.1073/pnas.1722100115
Wang Z, Kawaguchi K, Honda M, Hashimoto S, Shirasaki T, Okada H, Orita N, Shimakami T, Yamashita T, Sakai Y, Mizukoshi E, Murakami S, Kaneko S (2019) Notch signaling facilitates hepatitis B virus covalently closed circular DNA transcription via cAMP response element-binding protein with E3 ubiquitin ligase-modulation. Sci Rep 9(1):1621. https://doi.org/10.1038/s41598-018-38139-5
Wei X, Wang JP, Hao CQ, Yang XF, Wang LX, Huang CX, Bai XF, Lian JQ, Zhang Y (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. https://doi.org/10.3389/fcimb.2016.00132
Weihofen A, Binns K, Lemberg MK, Ashman K, Martoglio B (2002) Identification of signal peptide peptidase, a presenilin-type aspartic protease. Science 296(5576):2215–2218. https://doi.org/10.1126/science.1070925
Weihofen A, Lemberg MK, Friedmann E, Rueeger H, Schmitz A, Paganetti P, Rovelli G, Martoglio B (2003) Targeting presenilin-type aspartic protease signal peptide peptidase with gamma-secretase inhibitors. J Biol Chem 278(19):16528–16533. https://doi.org/10.1074/jbc.M301372200
Xu J, Chi F, Guo T, Punj V, Lee WN, French SW, Tsukamoto H (2015) NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J Clin Invest 125(4):1579–1590. https://doi.org/10.1172/JCI76468
Yang SL, Ren QG, Zhang T, Pan X, Wen L, Hu JL, Yu C, He QJ (2017) Hepatitis B virus X protein and hypoxia-inducible factor-1alpha stimulate Notch gene expression in liver cancer cells. Oncol Rep 37(1):348–356. https://doi.org/10.3892/or.2016.5211
Yang X, Xia W, Chen L, Wu CX, Zhang CC, Olson P, Wang XQ (2018) Synergistic antitumor effect of a gamma-secretase inhibitor PF-03084014 and sorafenib in hepatocellular carcinoma. Oncotarget 9(79):34996–35007. https://doi.org/10.18632/oncotarget.26209
Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, Shrestha K, Cahan P, Stanger BZ, Camargo FD (2014) Hippo pathway activity influences liver cell fate. Cell 157(6):1324–1338. https://doi.org/10.1016/j.cell.2014.03.060
Zeng J, Jing Y, Shi R, Pan X, Lai F, Liu W, Li R, Gao L, Hou X, Wu M, Wei L (2016) Autophagy regulates biliary differentiation of hepatic progenitor cells through Notch1 signaling pathway. Cell Cycle 15(12):1602–1610. https://doi.org/10.1080/15384101.2016.1181234
Zheng SP, Chen YX, Guo JL, Qi D, Zheng SJ, Zhang SL, Weng ZH (2013) Recombinant adeno-associated virus-mediated transfer of shRNA against Notch3 ameliorates hepatic fibrosis in rats. Exp Biol Med (Maywood) 238(6):600–609. https://doi.org/10.1177/1535370213480698
Zheng S, Zhang P, Chen Y, Zheng S, Zheng L, Weng Z (2016) Inhibition of Notch signaling attenuates Schistosomiasis hepatic fibrosis via blocking macrophage M2 polarization. PLoS One 11(11):e0166808. https://doi.org/10.1371/journal.pone.0166808
Zhu R, Yang J, Xu L, Dai W, Wang F, Shen M, Zhang Y, Zhang H, Chen K, Cheng P, Wang C, Zheng Y, Li J, Lu J, Zhou Y, Wu D, Guo C (2014) Diagnostic performance of Des-gamma-carboxy prothrombin for hepatocellular carcinoma: a meta-analysis. Gastroenterol Res Pract 2014:529314. https://doi.org/10.1155/2014/529314
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Kawaguchi, K., Kaneko, S. (2021). Notch Signaling and Liver Cancer. In: Reichrath, J., Reichrath, S. (eds) Notch Signaling in Embryology and Cancer. Advances in Experimental Medicine and Biology, vol 1287. Springer, Cham. https://doi.org/10.1007/978-3-030-55031-8_6
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