Sirolimus Attenuates Calcineurin Inhibitor-Induced Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma |
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| Institution: | 1. Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan;2. Medical-Engineering Hybrid Professional Development Center, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan;3. Division of Nucleic Acid Drug Development, Research Institute for Science and Technology, Tokyo University of Science, Chiba, Japan;4. Center for Preclinical Surgical and Interventional Research, Texas Heart Institute, Houston, Texas;5. Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan;1. State Institution “Heart Institute of the Ministry of Health of Ukraine”, Kyiv, Ukraine;2. Shupyk National Healthcare University of Ukraine, Kyiv, Ukraine;1. Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan;2. Department of Thoracic Surgery, Kyoto Katsura Hospital, Kyoto, Japan;1. Liver Transplant Institute, Inonu University Faculty of Medicine, Malatya, Turkey;2. Department of Medical Biochemistry, Inonu University Faculty of Medicine, Malatya, Turkey;3. Fuel-Oil Analysis Laboratory, Inonu University Rectorate, Malatya, Turkey;4. Department of Surgery, An-Najah National University Hospital, An-Najah National University, Nablus, Palestine;1. Inner Mongolia Medical University, Huhhot, China;2. Inner Mongolia Autonomous Region Tongliao City Hospital, Tongliao, China |
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| Abstract: | BackgroundCalcineurin inhibitors (CNIs), which are potent immunosuppressants (ISs), increase the risk for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LTx). Epithelial-mesenchymal transition (EMT) is a key process in which epithelial cancer cells lose their polarity, resulting in cancer progression and metastasis. The aim of this study was to evaluate the effect of sirolimus (SRL) individually and in combination with other ISs to reduce EMT.MethodsHCC SK-Hep1 cells were used and various ISs (SRL, tacrolimus, cyclosporine A, or mycophenolate mofetil) were administered at 2 dosages and in combination therapies. Mice were transplanted with SK-Hep1 cells (in the liver) and were monitored after 2 weeks.ResultsThe in vitro treatment with SRL showed a dose-dependent attenuation of cell proliferation and migration in case of the individual and IS combination treatments; further, decreased levels of pro-EMT proteins, namely, N-cadherin, transforming growth factor-β, ZEB1, Slug, and Snail were observed. In contrast, E-cadherin expression was upregulated after both the individual and IS combination treatments. These results were also observed in the samples from mice transplanted with the SK-Hep1 cells.ConclusionThe present study demonstrated that SRL reduced HCC metastasis by inhibiting EMT. Thus, our findings provide a rationale for the use of SRL in combination with ISs in HCC LTx patients. |
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