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      PPARγ activation reduces ischemia/reperfusion-induced metastasis in a murine model of hepatocellular carcinoma

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          Abstract

          Ischemia/reperfusion (I/R) injury during liver resection or transplantation for the treatment of hepatocellular carcinoma (HCC) may increase the risk of metastasis. Peroxisome proliferator-activated receptor-γ (PPARγ) activation has been observed to exert a protective effect against hepatic I/R injury. However, whether PPARγ activation exerts a protective effect against I/R-associated liver metastasis remains unknown. Therefore, the present study aimed to investigate the effects of the PPAR agonist rosiglitazone and the specific PPARγ antagonist GW9662 on tumor metastasis following hepatic I/R. An experimental mouse model of hepatic I/R-induced HCC metastasis was designed in order to determine the effects of I/R on tumor metastasis in the liver. Four groups were established: Sham, control (I/R), rosiglitazone (Ro) and rosiglitazone with GW9662 (Ro + GW) groups. In the latter two groups, the treatments were administered intravenously 1 h prior to the induction of ischemia. Tumor load was measured 12 days after the procedure. Furthermore, tissue analyses were conducted to determine the expression levels of alanine aminotransferase, myeloperoxidase (MPO), matrix metalloproteinase (MMP)-9, vascular cell adhesion molecule (VCAM)-1, nuclear factor (NF)-κB and PPARγ. Rosiglitazone pretreatment appeared to significantly mitigate hepatic I/R injury, as indicated by serological and histological analysis. The levels of VCAM-1, MPO and MMP-9 expression in the Ro group were significantly reduced at 8 h following ischemia compared with those in the control and Ro + GW groups. In addition, rosiglitazone inhibited the I/R-induced activation of NF-κB, and GW9662 attenuated the inhibitory effect. To the best of our knowledge, the present study is the first to report on the expression and the functional roles of PPARγ in I/R-associated metastasis. Short-term treatment of mice with rosiglitazone, a potent PPARγ agonist, confers protective effects against hepatic I/R-associated metastasis. Thus, PPARγ may be a potential therapeutic target for the protection of the liver against I/R-associated metastasis.

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          Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls.

          Nuclear factor kappaB (NF-kappaB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-kappaB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-kappaB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-kappaB in cancer, and the possible complications and pitfalls of such an approach, are explored.
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            Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis.

            Matrix metalloprotease type 9 (MMP-9) has been functionally implicated in VEGF activation, the induction and maintenance of chronic angiogenesis, and early stage tumor growth in a number of mouse models of cancer. In this article, we have identified two inflammatory cell types that are major sources of MMP-9 in the angiogenic stages of pancreatic islet carcinogenesis that unfold in RIP1-Tag2 transgenic mice. MMP-9-expressing neutrophils were predominantly found inside angiogenic islet dysplasias and tumors, whereas MMP-9-expressing macrophages were localized along the periphery of such lesions. Transient depletion of neutrophils significantly suppressed VEGF:VEGF-receptor association, a signature of MMP-9 activity, and markedly reduced the frequency of initial angiogenic switching in dysplasias. Thus infiltrating neutrophils can play a crucial role in activating angiogenesis in a previously quiescent tissue vasculature during the early stages of carcinogenesis.
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              Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis.

              Nuclear factor-kappaB (NF-kappaB) is a transcriptional regulator of genes involved in immunity, inflammatory response, cell fate, and function. Recent attention has focused on the pathophysiological role of NF-kappaB in the diseased liver. In vivo studies using rodent models of liver disease and cell-targeted perturbation of NF-kappaB activity have revealed complex and multicellular functions in hepatic inflammation, fibrosis, and the development of hepatocellular carcinoma - a process we have termed the "inflammation-fibrosis-cancer axis". This review summarizes the current state of knowledge and provides insight into the vast complexity of the hepatic NF-kappaB signaling system, which should provide a rich source of new therapeutic targets.
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                Author and article information

                Journal
                Exp Ther Med
                Exp Ther Med
                ETM
                Experimental and Therapeutic Medicine
                D.A. Spandidos
                1792-0981
                1792-1015
                February 2016
                11 December 2015
                11 December 2015
                : 11
                : 2
                : 387-396
                Affiliations
                [1 ]Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
                [2 ]Department of Hepatobiliary Surgery, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R. China
                [3 ]Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
                Author notes
                Correspondence to: Dr Jiahong Dong, Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, 107 Wenhua West Road, Jinan, Shangdong 250012, P.R. China, E-mail: dong_jiahong@ 123456126.com
                Article
                ETM-0-0-2934
                10.3892/etm.2015.2934
                4734081
                26893620
                8f6b80e6-53ed-4182-b1a3-9e1f41d0eedc
                Copyright: © Liu et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 21 July 2014
                : 19 August 2015
                Categories
                Articles

                Medicine
                hepatic metastasis,peroxisome proliferator-activated receptor-γ,ischemia/reperfusion,rosiglitazone

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