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Xu D.,Nanjing Medical University | Wang X.,Nanjing Medical University | Yan S.,Nanjing Medical University | Yin Y.,Nanjing Medical University | And 3 more authors.
Tumor Biology | Year: 2014

Protein tyrosine phosphatase receptor type O (PTPRO) has been identified as a tumor suppressor in a number of cancers including hepatocellular carcinoma (HCC). Toll-like receptor 4 (TLR4) plays diverse roles in HCC tumorigenesis and progression. The association between PTPRO and TLR4 signaling in HCC remains largely unknown. We aimed to clarify the interaction between PTPRO and TLR4 in HCC. Surprisingly, we found reduced and positive-related expression of TLR4 and PTPRO in 84 human HCC specimens. Increased TLR4 expression and activity was found in PTPRO-overexpressed HCC cells stimulated with lipopolysaccharide (LPS). The feedback regulation of PTPRO and TLR4 was dependent on nuclear factor-κB (NF-κB) activation, as suggested by NF-κB inhibition and luciferase reporter assay. Our study suggests that the effect of PTPRO on TLR4 signaling is dependent on NF-κB pathway, suggesting an interesting PTPRO/TLR4/NF-κB signaling feedback loop in HCC carcinogenesis and progression. © International Society of Oncology and BioMarkers (ISOBM) 2014.

Lu L.,Saban Research Institute | Lu L.,Key Laboratory of Living Donor Liver Transplantation | Ma J.,Immunology and Nephrology | Li Z.,CAS Institut Pasteur of Shanghai | And 15 more authors.
PLoS ONE | Year: 2011

Background: It has been documented all-trans retinoic acid (atRA) promotes the development of TGF-β-induced CD4 +Foxp3 + regulatory T cells (iTreg) that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs. Methodology/Principal Findings: Addition of atRA to naïve CD4 +CD25 - cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3 + iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-β-treated CD4 + cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-β-treated CD4 + cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4 + cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4 + cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS) elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered. Conclusions/Significance: We have identified the cellular and molecular mechanism(s) by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation. © 2011 Lu et al.

Li X.,Nanjing Medical University | Xu H.,Nanjing Medical University | Dai X.,Key Laboratory of Living Donor Liver Transplantation | Dai X.,Nanjing Medical University | And 3 more authors.
International Journal of Nanomedicine | Year: 2012

Paclitaxel (Ptx), one of the most widely used anticancer agents, has demonstrated extraordinary activities against a variety of solid tumors. However, the therapeutic response of Ptx is often associated with severe side effects caused by its nonspecific cytotoxic effects and special solvents (Cremophor EL®). The current study reports the stable controlled release of Ptx/tetrandrine (Tet)-coloaded nanoparticles by amphilic methoxy poly(ethylene glycol)-poly(caprolactone) block copolymers. There were three significant findings. Firstly, Tet could effectively stabilize Ptx-loaded nanoparticles with the coencapsulation of Tet and Ptx. The influence of different Ptx/Tet feeding ratios on the size and loading efficiency of the nanoparticles was also explored. Secondly, the encapsulation of Tet and Ptx into nanoparticles retains the synergistic anticancer efficiency of Tet and Ptx against mice hepatoma H22 cells. Thirdly, in the in vivo evaluation, intratumoral administration was adopted to increase the site-specific delivery. Ptx/Tet nanoparticles, when delivered intratumorally, exhibited significantly improved antitumor efficacy; moreover, they substantially increased the overall survival in an established H22-transplanted mice model. Further investigation into the anticancer mechanisms of this nanodelivery system is under active consideration as a part of this ongoing research. The results suggest that Ptx/Tet-coloaded nanoparticles could be a potential useful chemotherapeutic formulation for liver cancer therapy. © 2012 Cárdenas et al, publisher and licensee Dove Medical Press Ltd.

Dong T.,Peoples Hospital of Jiangsu Province | Yan Y.,Nanjing Medical University | Chai H.,Nanjing Medical University | Chen S.,Nanjing Medical University | And 5 more authors.
Biomedicine and Pharmacotherapy | Year: 2015

Cancer cells consume large amounts of glucose to produce lactate, even in the presence of ample oxygen. This phenomenon is known as the Warburg effect. The pyruvate kinase promotes aerobic glycolysis, and the pyruvate kinase M2 isoform (PKM2) is highly expressed in many cancer cells. Although the Warburg effect is a hallmark of cancer, the mechanism by which PKM2 contributes to the Warburg effect, and its role in tumor growth remain to be defined. We proposed that PKM2 activates transcription of hypoxia inducible factor-1α (HIF-1α) by phosphorylating STAT3 (signal transducer and activator of transcription 3) at Y705 (tyrosine 705) as a plausible mechanism for liver cancer cell proliferation. In the current study, we observed that PKM2 was over-expressed in hepatocellular carcinoma (HCC) tissues compared to adjacent normal tissues. The experiments further indicate that nuclear PKM2 is an active protein kinase in cultured cells. Knockdown of PKM2 affected the levels of HIF-1α and Bcl-xL (B-cell lymphoma-extra large), suggesting that PKM2 plays an important role in promoting cell proliferation. In conclusion, the current findings demonstrate that PKM2 is an active protein kinase, and promotes liver cancer cell proliferation by up-regulating HIF-1α and Bcl-xL expression. © 2015 Elsevier Masson SAS.

Wu Z.,Nanjing Medical University | Wu Z.,Key Laboratory of Living Donor Liver Transplantation | Qin J.,Nanjing Medical University | Qin J.,Key Laboratory of Living Donor Liver Transplantation | And 2 more authors.
Journal of Biomedical Research | Year: 2012

Omega-3 fatty acid supplemented total parenteral nutrition improves the clinical outcome of patients undergoing certain operations; however, its benefits for patients with hepatitis type B virus (HBV)-associated hepatocellular carcinoma (HCC) who have undergone hepatectomy are still not clear. The aim of this study was to evaluate the effect of omega-3 fatty acid supplemented total parenteral nutrition on the clinical outcome of patients with HBV-associated HCC who underwent hepatectomy at our institution. A total of 63 patients with HBV-associated HCC who underwent hepatectomy were included in this study. These patients were randomly assigned to receive standard total parenteral nutrition (the control group, n = 31) or omega-3 fatty acid supplemented total parenteral nutrition (the omega-3 fatty acid group, n = 32) for at least 5 d. The study endpoints were the occurrence of infection-related complications, recovery of liver function and length of hospital stay. The results showed that the omega-3 fatty acid group had a lower infection rate (omega-3 fatty acid, 19.4% vs control, 43.8%, P < 0.05), a better liver function after hepatectomy: alanine transaminase (omega-3 fatty acid, 48.23±18.48 U/L vs control, 73.34±40.60 U/L, P < 0.01), aspartate transaminase (omega-3 fatty acid, 35.77±14.56 U/L vs control, 50.53±24.62 U/L, P < 0.01), total bilirubin (omega-3 fatty acid, 24.29±7.40 mmol/L vs control, 28. 37±8.06 mmol/L, P < 0.05) and a shorter length of hospital stay (omega-3 fatty acid, 12.71±2.58 d vs control, 15.91±3.23 d, P < 0.01). The serum contents of IL-6 (omega-3 fatty acid, 23.98±5.63 pg/mL vs control, 35.55±7.5 pg/mL, P < 0.01) and TNF-α (omega-3 fatty acid, 4.43±1.22 pg/mL vs control, 5.96±1.58 pg/mL, P < 0.01) after hepatectomy were significantly lower in the omega-3 fatty acid group than those of the control group. In conclusion, administration of omega-3 fatty acid may reduce infection rate and improve liver function recovery in HBV-associated HCC patients after hepatectomy. This improvement is associated with suppressed production of proinflammatory cytokines in these patients. © 2012 The Editorial Board of Journal of Biomedical Research.

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