Investigating IFN-gamma Susceptibility and Oncogenic Regulation in Gastric Cancer Cells

  • 曾 柏鈞

Student thesis: Doctoral Thesis


AKT regulates activated glycogen synthase kinase (GSK)-3β to facilitate IFN-γ signaling through the inhibition of Src homology-2 domain-containing phosphatase (SHP) 2 Mutated phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) cause AKT activation and GSK-3β inactivation to induce SHP2-activated cellular hyporesponsiveness to IFN-γ in human gastric cancer AGS cells Here we want to discover whether some molecules for promoting AKT activation GSK-3β inactivation and SHP2 activation to cause IFN-γ resistance First the potential role of galectin-3 acts upstream of AKT will be investigated Increasing or decreasing galectin-3 could change IFN-γ signaling Following cisplatin-induced galectin-3 up-regulation surviving cells showed cellular hyporesponsiveness to IFN-γ Galectin-3 induced IFN-γ resistance independent of its extracellular β-galactoside-binding activity Galectin-3 expression was not regulated by PI3K activation or a decrease in PTEN Increased galectin-3 might cause GSK-3β inactivation and SHP2 activation by promoting PDK1-induced AKT phosphorylation at a threonine residue Overexpression of AKT inactive GSK-3βR96A SHP2 or active SHP2D61A caused cellular hyporesponsiveness to IFN-γ in IFN-γ-sensitive MKN45 cells IFN-γ-induced growth inhibition and apoptosis in AGS cells were observed until galectin-3 expression was down-regulated In the first part these results demonstrate that an increase in galectin-3 facilitates AKT/GSK-3β/SHP2 signaling causing cellular hyporesponsiveness to IFN-γ Integrin-linked kinase (ILK) a serine/ threonine kinase regulates cell adhesion migration and proliferation also particularly by promoting AKT signaling However aberrant increased ILK did not affect AKT/GSK-3β and IFN-γ-activated IRF1 indicating ILK does not contribute to IFN-γ resistance The role of ILK regulation is not clearly in AGS cells Previous study shows that ILK increased in gastric cancer is correlated with tumor grade and metastasis The regulation for ILK overexpression and mechanisms for ILK-regulated gastric tumorigenesis has not documented We next want to identify the molecular basis for ILK regulation and its alternative role in the ERK1/2/NF-κB-mediated stimulation of proliferation migration and survival Genetically or pharmacologically inhibiting ILK abolished NF-κB-regulated cell proliferation Unpredictably ILK stimulated Ras activity by facilitating the activation of c-Raf/MEK1/2/ERK1/2/ribosomal S6 kinase/inhibitor of κB?/NF-κB signaling by a complex of IQ motif containing GTPase activating protein (IQGAP) 1 and Ras Enforced enzymatic ILK expression promoted cell proliferation by facilitating ERK1/2/NF-κB signaling PI3K activation or the decreased expression of PTEN prolonged ERK1/2 activation through the protection of ILK from proteasome-mediated degradation The C-terminus of heat shock cognate 70 interacting protein a HSP90-associated E3 ubiquitin ligase mediated ILK ubiquitination to control PI3K- and HSP90-regulated ILK stabilization and signaling In addition to proliferation this pathway also determined cell migration and restricted the sensitivity of anticancer agents to 5-fluorouracil and cisplatin Additionally validating EGF/EGFR signaling confirmed the ERK-regulatory roles of ILK and IQGAP1 These results demonstrate that an increase in ILK facilitates IQGAP1 and Ras interaction and non-canonically promotes ERK1/2/NF-κB activation to benefit cell growth Taken together we investigate IFN-γ susceptibility and oncogenic regulation in gastric cancer cells
Date of Award2016 Jan 27
Original languageEnglish
SupervisorYan-Shen Shan (Supervisor)

Cite this