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Chen W.,Sun Yat Sen University | Chen W.,Guangdong Provincial Key Laboratory of Liver Disease Research | Wu Y.,Sun Yat Sen University | Liu W.,Guangdong Provincial Key Laboratory of Liver Disease Research | And 10 more authors.
Cancer Letters | Year: 2011

Oncolytic adenoviruses may offer a new treatment option and improve the prognosis for patients with hepatocellular carcinoma (HCC). However, the antitumor efficacy of oncolytic adenoviruses on HCC cells is compromised due to low expression of the adenovirus serotype 5 (Ad5) receptor on the target cells. In this study we showed that all HCC cell lines and clinical samples expressed high level of CD46, the receptor for Adenovirus 35 (Ad35) and constructed new fiber chimeric oncolytic adenoviruses with or without a p53 gene expression cassette, SG635-p53 and SG635, respectively. These variants were derived from the previously described Ad5 vectors SG600-p53 and SG600 by replacing the Ad5 fiber with a chimeric Ad5/35 fiber. It was found that the 5/35 fiber chimeric adenovirus vector (Ad5/35-EGFP) demonstrated significantly improved transduction in all tested HCC cell lines compared with the Ad5 vector (Ad5-EGFP). The new fiber chimeric oncolytic adenoviruses produced more progeny viruses in HCC cells than did the Ad5-based viruses but replicated weakly in normal fibroblast BJ cells. In addition, SG635-p53 mediated a higher level of transgenic expression than SG600-p53 in Hep3B and Huh7 cells and showed a markedly enhanced antitumor effect on HCC cells in vitro compared with SG635 or SG600-p53 without causing significant cytotoxicity to normal cells. Antitumor activity of SG635-p53 was shown in Hep3B subcutaneous xenograft tumor models following intratumoral injection, resulting in significant inhibition of tumor growth and prolonged survival of animals. Our data suggest that SG635-p53, as a fiber chimeric oncolytic adenovirus in combination with p53 expression, may serve as a novel, promising and safe anticancer agent for the treatment of HCC. © 2011 Elsevier Ireland Ltd.


Wang G.-Y.,Sun Yat Sen University | Yang Y.,Sun Yat Sen University | Li H.,Sun Yat Sen University | Zhang J.,Sun Yat Sen University | And 4 more authors.
Hepatology Research | Year: 2012

Aim: To determine whether donor immature dendritic cells (imDCs) combined with a short postoperative course of rapamycin (Rapa) has the ability to expand the CD4 +CD25 +Foxp3 + regulatory T (Treg) cells and prolong liver allograft survival. Methods: Orthotopic liver transplantation (OLT) was performed from Lewis rats to Brown Norway recipients. Three days before transplantation, animals were injected intravenously with 2×10 6 donor bone marrow-derived imDCs. Recipient rats (the combined treated group) also received Rapa for 7 d after liver transplantation. Additional groups received either imDCs alone, Rapa alone, or saline alone. Every six recipients from each group were killed at 14days, 28days after OLT. The changes of CD4 +CD25 +Foxp3 + Treg cells in peripheral blood and spleen, histological changes of liver grafts, and serum cytokine levels were investigated. The other six recipients were left in each group to observe the animal survival. Results: Donor imDCs followed by a short postoperative course of Rapa induced long-term allograft survival. The percentage of CD4 +CD25 +Foxp3 + Treg cells in CD4 + T cells in the combination treatment group were significantly higher compared with the acute rejection group. Moreover, within the CD4 +CD25 + T cell population the combination treatment recipients maintained a higher incidence of Foxp3 + T cells compared with the other groups. Despite the lower serum levels of interleukin (IL)-2, IL-12, and interferon-γ in the combined treated group, the cytokine levels in the combined treated group at 7days after OLT was nearly twice that at 3days after OLT but decreased significantly compared with the other groups at 28days after OLT. Serum IL-10 level in the combined treated group was higher than the other groups. Conclusions: A single imDC infusion followed by a short postoperative course of Rapa prolongs liver allograft survival and enhances the expansion of Treg cells. This optimal protocol may be a promising administration protocol for the peritransplant tolerance induction. © 2011 The Japan Society of Hepatology.


Deng Y.,Sun Yat Sen University | Deng Y.,Guangdong Provincial Key Laboratory of Liver Disease Research | Yi S.,Sun Yat Sen University | Wang G.,Sun Yat Sen University | And 15 more authors.
Stem Cells and Development | Year: 2014

The mechanisms responsible for the inhibitory effects of mesenchymal stem cells (MSCs) on dendritic cells (DCs) are still poorly understood. Our investigation of the potential signaling pathways revealed for the first time that human umbilical-cord-derived MSCs (UC-MSCs) instruct DCs to acquire tolerogenic phenotypes through the IL-6-mediated upregulation of SOCS1. This subset of MSC-DCs exhibited a tolerogenic pattern, with a clear decrease in the expression of co-stimulatory molecules and the capacity to stimulate CD3 + T cell proliferation and inflammatory factor secretion, and a significant increase in the production of inhibitory cytokine IL-10 and the ability to induce Treg cells and Th2 responses. Adoption of this tolerogenic pattern required the activation of SOCS1, which blocked DC maturation by impairing TLR4 signaling. The effects of UC-MSCs on SOCS1 activation were essentially mediated by the JAK-STAT pathway via IL-6 secretion. In summary, our data identify a new mechanism, involving the IL-6-mediated upregulation of SOCS1, by which UC-MSCs instruct DCs to acquire tolerogenic phenotypes. © 2014, Mary Ann Liebert, Inc.


Li T.,Sun Yat Sen University | Li T.,Guangdong Provincial Key Laboratory of Liver Disease Research | Yang Y.,Sun Yat Sen University | Hua X.,Sun Yat Sen University | And 10 more authors.
Cancer Letters | Year: 2012

Defects in natural killer (NK) cell function are necessary for tumor immune escape, but the underlying regulatory mechanisms in human cancers remain largely unknown. Here we show that fibroblasts derived from hepatocellular carcinoma (HCC) were significantly superior to foreskin-derived fibroblasts at inducing NK cell dysfunction, which is characterized by low expression of cytotoxic molecules and surface markers for cell activation, impaired production of cytokines, and decreased cytotoxicity against K562 cells in vitro. Our results also indicate that PGE2 and IDO, derived from activated fibroblasts, suppress the activation of NK cells and thereby create favorable conditions for tumor progression. © 2011 Elsevier Ireland Ltd.


Ye X.,Sun Yat Sen University | Ye X.,Guangdong Provincial Key Laboratory of Liver Disease Research | Guo Y.,Sun Yat Sen University | Guo Y.,Guangdong Provincial Key Laboratory of Liver Disease Research | And 10 more authors.
PLoS ONE | Year: 2013

βKlotho is a regulator in multiple metabolic processes, while its role in cancer remains unclear. We found the expression of βKlotho was down-regulated in human hepatocellular carcinoma tissues compared with that in paired adjacent non-tumourous liver tissues. Hepatoma cells also showed decreased expression of βKlotho compared with normal hepatocyte cells. Reintroduction of βKlotho into hepatoma cells inhibited their proliferation. The anti-proliferative effect of βKlotho might be linked with G1 to S phase arrest, which was mediated by Akt/GSK-3β/cyclin D1 signaling, since forced expression βKlotho reduced the phosphorylation level of Akt and GSK-3β and induced down-regulation of cyclin D1. Furthermore, βKlotho overexpression could inhibit tumorgenesis, while constitutively activated Akt could override the suppressive effects of βKlotho in vivo. These data suggest βKlotho suppresses tumor growth in hepatocellular carcinoma. © 2013 Ye et al.


Wang G.-Y.,Sun Yat Sen University | Yang Y.,Sun Yat Sen University | Li H.,Sun Yat Sen University | Zhang J.,Sun Yat Sen University | And 6 more authors.
PLoS ONE | Year: 2011

Background: Neutrophil to lymphocyte ratio (NLR) has been proposed to predict prognosis of hepatocellular carcinoma (HCC). However, the cut-off values are empirical. We determined the optimal cut-off value to predict HCC recurrence after liver transplantation (LT) and further established a scoring model based on NLR. Methodology/Principal Findings: We analyzed the outcome of 101 HBV-associated HCC patients undergoing LT. Preoperative risk factors for tumor recurrence were evaluated by univariate analysis. By using ROC analysis, NLR≥3 was considered elevated. The disease-free survival (DFS) and overall survival (OS) for patients with high NLR was significantly worse than that for patients with normal NLR (the 5-year DFS and OS of 28.5% and 19.5% vs. 64.9% and 61.8%, respectively; P<0.001). Univariate analysis revealed that tumor size >5 cm, tumor number >3, macrovascular invasion, AFP≥400 μg/L, NLR≥3, and HBV-DNA level >5 log10 copies/mL were preoperative predictors of DFS. Cox regression analysis showed macrovascular invasion, tumor number, and high NLR were independent prognostic factors. We then established a preoperative prognostic score based on multivariate analysis. Each factor was given a score of 1. Area under the ROC curve of the score was 0.781. All nine patients with score 3 developed recurrence within 6 months after LT. Of 71 patients without vascular invasion, three patients with both tumor number >3 and NLR≥3 developed recurrence within 14 months after LT while the 5-year DFS and OS for patients with a score of 0 or 1 were 68.1% and 62.8%, respectively. Conclusions/Significance: Preoperative elevated NLR significantly increases the risk of recurrence in patients underwent LT for HCC. Patients with both NLR≥3 and tumor number >3 are not a good indication for LT. Our score model may aid in the selection of patients that would most benefit from transplantation for HCC. © 2011 Wang et al.


Yan J.,Southern Medical University | Liu X.-L.,Southern Medical University | Xiao G.,Southern Medical University | Li N.-L.,Southern Medical University | And 6 more authors.
PLoS ONE | Year: 2014

Background and Aims: An immune imbalance in the cytokine profile exerts a profound influence on the progression of hepatitis B virus (HBV) infections and hepatocellular carcinoma (HCC). The present study evaluated the immune status of T helper (Th) 17 and Th1 cells in patients with HBV-related and non-HBV-related HCC. Methods: We randomly enrolled 150 patients with HCC. Blood samples and tissue samples were obtained. The distributions and phenotypic features of Th17 and Th1 cells were determined by flow cytometry and/or immunohistochemistry. Results: Compared to corresponding non-tumor regions, the levels of Th17 and Th1 cells were significantly increased in tumors of patients with HCC (P<0.001). The intratumoral densities of IL-17-producing cells and IFN-γ-producing cells were associated with overall survival (OS, P = 0.001) and disease-free survival (DFS, P = 0.001) of patients with HCC. The ratio of Th17 to Th1 in HBV-related HCC was higher than in non-HBV-related HCC. A multivariate Cox analysis revealed that the Th17 to Th1 ratio was an independent prognostic factor for OS (HR = 2.651, P = 0.007) and DFS (HR = 2.456, P = 0.002). Conclusions: HBV infections can lead to an imbalance in immune status in patients with HCC. An elevated Th17 to Th1 ratio may promote tumor progression. The Th17 to Th1 ratio could serve as a potential prognostic marker for scoring the severity of HCC. © 2014 Yan et al.


PubMed | Guangdong Provincial Key Laboratory of Liver Disease Research and Sun Yat Sen University
Type: Journal Article | Journal: Biochemical and biophysical research communications | Year: 2016

Transducin-Like Enhancer of Split protein 4 (TLE4) has been reported to be involved in some subsets of acute myeloid leukemia and colorectal cancer. In the present study, we aimed to explore the role of TLE4 in tumorigenesis and cancer progression in hepatocellular carcinoma (HCC).The expression pattern of TLE4 in HCC was determined by Western-blot and qRT-PCR, gain-of-function and loss-of-function was used to explore the biological role of TLE4 in HCC cells. A xenograft model was established to confirm its effects on proliferation.The protein expression levels of TLE4 were significantly down-regulated in HCC tissues compared to matched adjacent normal liver tissues. Invitro, down-regulation of TLE4 in Huh7 or SMMC-7721 promoted cell proliferation and ectopical expression of TLE4 in Hep3B or Bel-7404 suppressed cell proliferation. In addition, the cell colony formation ability was enhanced after down-regulation of TLE4 expression in Huh-7 but suppressed after over-expression in Hep3B. Furthermore, down-regulation of TLE4 increased the cell invasion ability, as well as increased the expression level of Vimentin and decreased that of E-cadherin, indicating a phenotype of epithelial-mesenchymal transition (EMT) in HCC cells. On the contrary, ectopical expression of TLE4 in HCC cells decreased the cell invasion ability and inhibited EMT. Invivo, compared to control group, xenograft tumor volumes were significantly decreased in TLE4 overexpression group.These results demonstrated that TLE4 might play important regulatory roles in cellular proliferation and EMT process in HCC.


PubMed | Guangdong Provincial Key Laboratory of Liver Disease Research and Sun Yat Sen University
Type: | Journal: Oncogenesis | Year: 2016

Although carcinoma-associated fibroblasts (CAFs) in tumor microenvironments have a critical role in immune cell modulation, their effects on the generation of regulatory dendritic cells (DCs) are still unclear. In this study, we initially show that CAFs derived from hepatocellular carcinoma (HCC) tumors facilitate the generation of regulatory DCs, which are characterized by low expression of costimulatory molecules, high suppressive cytokines production and enhanced regulation of immune responses, including T-cell proliferation impairment and promotion of regulatory T-cell (Treg) expansion via indoleamine 2,3-dioxygenase (IDO) upregulation. Our findings also indicate that STAT3 activation in DCs, as mediated by CAF-derived interleukin (IL)-6, is essential to IDO production. Moreover, IDO inhibitor, STAT3 and IL-6 blocking antibodies can reverse this hepatic CAF-DC regulatory function. Therefore, our results provide new insights into the mechanisms by which CAFs induce tumor immune escape as well as a novel cancer immunotherapeutic approach (for example, targeting CAFs, IDO or IL-6).


PubMed | German Cancer Research Center, Guangdong Provincial Key Laboratory of Liver Disease Research and Southern Medical University
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

Elevated levels of neutrophils have been associated with poor survival in various cancers, but direct evidence supporting a role for neutrophils in the immunopathogenesis of human cancers is lacking.A total of 573 patients with gastric cancer were enrolled in this study. Immunohistochemistry and real-time PCR were performed to analyze the distribution and clinical relevance of neutrophils in different microanatomic regions. The regulation and function of neutrophils were assessed both in vitro and in vivo RESULTS: Increased neutrophil counts in the peripheral blood were associated with poor prognosis in gastric cancer patients. In gastric cancer tissues, neutrophils were enriched predominantly in the invasive margin, and neutrophil levels were a powerful predictor of poor survival in patients with gastric cancer. IL17These data provide direct evidence supporting the pivotal role of neutrophils in gastric cancer progression and reveal a novel immune escape mechanism involving fine-tuned collaborative action between cancer cells and immune cells in the distinct tumor microenvironment. Clin Cancer Res; 1-11. 2016 AACR.

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