fig2

Figure 2. Non-energetic roles of glucose in the progression of CCA. Apart from being metabolized in glycolysis to yield ATP, glucose can be shunted to the hexosamine biosynthetic pathway to be a precursor for GlcNAc synthesis. GlcNAc is utilized in an O-GlcNAcylation, which alters the stability of several oncoproteins and hence promotes the aggressive phenotypes of CCA cells. On the other hand, glucose can activate several intracellular signaling pathways such as GSK3β/β-Cat, JAK2/STAT3, and NF-κB. Moreover, high glucose also upregulates IL-1β and IL-6, which are the upstream activators of those signaling pathways. Altogether, these mechanisms explain in part how diabetogenic glucose promotes CCA progression. However, the in-depth molecular mechanisms remain elucidated. VIM: Vimentin; FOXO3: Forkhead Box O3; MAN1A1: Mannosidase Alpha Class 1A Member 1; hnRNPK: Heterogeneous Nuclear Ribonucleoprotein K; CCND1: cyclin D1; CCNA: cyclin A; MMP2: matrix metalloproteinase-2; MMP7: matrix metalloproteinase-7; CCA: cholangiocarcinoma; GlcNAc: N-acetylglucosamine; O-GlcNAcylation: O-link GlcNAc glycosylation; GSK3β/β-Cat: glycogen synthase kinase-3β/β-catenin; JAK2/STAT3: Janus kinase 2/signal transducer and activator of transcription 3; NF-κB: nuclear factor-κB; IL-1β: interleukin-1β; IL-6: interleukin-6.