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Permanent URI for this collectionhttps://hdl.handle.net/11443/932
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Item Role of FLT3 in the proliferation and aggressiveness of hepatocellular carcinoma(Scientific and Technological Research Council Turkey, 2016-01-01) Aydin, Muammer Merve; Bayin, Nermin Sumru; Acun, Tolga; Yakicier, Mustafa Cengiz; Akcali, Kamil CanBackground/aim: Previously we showed that Fms-like tyrosine kinase (FLT3) changes its cellular localization upon partial hepatectomy, suggesting a role in liver regeneration. FLT3 was also shown to play an important function in cellular proliferation and activation of PI3K and Ras. Thus, we aimed to investigate the role of FLT3 in hepatocellular tumorigenesis utilizing in vitro and in vivo models. Materials and methods: We used Snu398 cells that express FLT3. We investigated these cells' in vitro proliferation and invasion abilities by treatment with the FLT3 inhibitor K-252a or by knocking-down with FLT3 shRNA,. Furthermore, the effect of blocking FLT3 activity and expression during in vivo tumorigenesis was assessed with xenograft models. Results: After K-252a treatment or stable knock-down, these cells' proliferation and migration abilities were highly diminished in vitro. In addition, significant diminution in tumorigenicity of Snu398 cells was also obtained in vivo. When FLT3 knocked-down Snu398 cells were injected into nude mice, we did not detect aSMA expression in these tumors, suggesting a role for FLT3 in in vivo invasiveness. Conclusion: Our data provided evidence that FLT3 has a crucial role both in hepatocarcinogenesis and its invasiveness. Therefore, targeting FLT3 and/or its activity may be a promising tool for combating hepatocellular carcinomas.Item Increased free Zn2+ correlates induction of sarco(endo)plasmic reticulum stress via altered expression levels of Zn2+-transporters in heart failure(WILEY, 2018-01-01) Olgar, Yusuf; Durak, Aysegul; Tuncay, Erkan; Bitirim, Ceylan Verda; Ozcinar, Evren; Inan, Mustafa Bahadir; Tokcaer-Keskin, Zeynep; Akcali, Kamil Can; Akar, Ahmet Ruchan; Turan, BelmaZn2+-homoeostasis including free Zn2+ ({[}Zn2+](i)) is regulated through Zn2+-transporters and their comprehensive understanding may be important due to their contributions to cardiac dysfunction. Herein, we aimed to examine a possible role of Zn2+-transporters in the development of heart failure (HF) via induction of ER stress. We first showed localizations of ZIP8, ZIP14 and ZnT8 to both sarcolemma and S(E)R in ventricular cardiomyocytes (H9c2 cells) using confocal together with calculated Pearson's coefficients. The expressions of ZIP14 and ZnT8 were significantly increased with decreased ZIP8 level in HF. Moreover, {[}Zn2+](i) was significantly high in doxorubicin-treated H9c2 cells compared to their controls. We found elevated levels of ER stress markers, GRP78 and CHOP/Gadd153, confirming the existence of ER stress. Furthermore, we measured markedly increased total PKC and PKC alpha expression and PKC alpha-phosphorylation in HF. A PKC inhibition induced significant decrease in expressions of these ER stress markers compared to controls. Interestingly, direct increase in {[}Zn2+](i) using zinc-ionophore induced significant increase in these markers. On the other hand, when we induced ER stress directly with tunicamycin, we could not observe any effect on expression levels of these Zn2+ transporters. Additionally, increased {[}Zn2+](i) could induce marked activation of PKC alpha. Moreover, we observed marked decrease in {[}Zn2+](i) under PKC inhibition in H9c2 cells. Overall, our present data suggest possible role of Zn2+ transporters on an intersection pathway with increased {[}Zn2+](i) and PKC alpha activation and induction of HF, most probably via development of ER stress. Therefore, our present data provide novel information how a well-controlled {[}Zn2+](i) via Zn2+ transporters and PKC alpha can be important therapeutic approach in prevention/treatment of HF.