Copyright ©The Author(s) 2020.
World J Gastrointest Oncol. Sep 15, 2020; 12(9): 957-974
Published online Sep 15, 2020. doi: 10.4251/wjgo.v12.i9.957
Table 1 List of main representatives of Notch Signalling pathway and their current findings in development of cholangiocarcinoma
Receptors, ligands and downstream signaling moleculesType of modelFindingsRef.  
Notch 1Mice modelOverexpression of NICD1 in mice liver leads to the formation of cystoadenomas and cystoadenocarcinomas. IH-CCA cell migration is enhanced by overexpression of Notch 1. It further enhances the growth of IH-CCA as result of Rac1 activation. The atypical expression by the up-regulation of Vimentin and α-SMA at the expense of E-cadherin expression leads to an EMT[32,63]
Human cell linesOverexpression of Notch 1 receptor along with JAG-1 has been perceived in four human CCA cell lines (MzChA1, TFK1, SZ1and EgI1)[61]
Notch 2Wild-type and Notch2 flox/floxmice modelNotch2 is basically involved in regulating the hepatocyte derived CCA. Wild-type and Notch2 flox/floxmice models have been utilized for studying the Notch Signalling pathway in AKT/Yap-driven IH-CCA development and has been found that AKT/Yap-induced IH-CCA development is hepatocyte dependent and based on the canonical Notch signalling cascade in in vivo models[14]
Human cell linesHCC and ICC cell lines reveals the down-regulation in expression of Sox9 and EpCAM, typical biliary markers after Notch 2 silencing[14]
Notch 3Mice modelIH-CCA development and survival has been found to be associated with activation of PI3K-AKT cascade by overexpression of the Notch 3 atypical receptor rather than canonical Notch-RBPJ mechanism. Hepatocarcinogen Thioacetamide induces cancer in CK19CreERTeYFPp53 mouse model owing constitutive Notch3 deletion that establishes the IH-CCA inhibition after loss of single copy of Notch 3 gene[66,62]
Notch 4Human samplesThe overexpression of Notch 4 is associated with raised serum levels of CA125 that suggests the poor prognosis of IH-CCA[59]
Jagged-1Human cell linesThe suppression of the Jagged-1 results in the reduction of growth of the human CCA cell lines (HUCCT1 and KKU-156) with consequent down-regulation of downstream signalling molecules (Hes1 and Hes4)[16]
RBPJMice modelThe down-regulation of RBPJ protein in AKT/JAG-1 mouse model results in total inhibition of Notch signalling pathway following the development of IH-CCA. Notch 1 plays its role in advancement of CCA by enhancing the cell survival and proliferation through the regulation of 14-3-3 theta in RBP-J-associated module. Hence, it concludes that that RBPJ is a significant element in Notch signalling pathway in CCA[16,70]
Hes-1Mice modelThe tamoxifen-inducible Alb CreERT2; R26R Notch/+ mice expresses mouse NICD1 and delivers the constitutive Notch activity in hepatic cells. In Alb-CreERT2;Hes1fl/fl mice, these hepatocytes that lack the Hes1 gene have revealed that on treatment with TAA, CK10 positive cells significantly increases in lobules of Alb CreERT2; R26RNotch/+ and has been found to be reduced in Alb-CreERT2; Hes1fl/fl mice. Besides that, the rapid nodule formation has been found to be obvious in the livers of Alb CreERT2; R26RNotch/+ in contrast to those of Alb-CreERT2; Hes1fl/fl.. This observation confirms the fact that Hes1 is greatly involved in pathogenicity of IH-CCA. Further, this carcinogenesis can be blocked by inhibition of Hes1[73,74]