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ABSTRACT: To investigate the impact of different anesthetic techniques on T-helper (Th) cell subsets in hepatocellular carcinoma (HCC) patients undergoing hepatectomy.
Sixty-one HCC patients who received hepatectomies were randomized into an epidural combined general anesthesia (G + E; n = 31) or a general anesthesia (G; n = 30) group. Blood samples were obtained the morning before the operation (d0), and on the second (d2) and seventh (d7) day after the operation. Th cell contents were evaluated using flow cytometry, real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay.
In all 61 patients, Th1 and Th2 cell frequencies, and interferon-γ (IFN-γ) mRNA expression markedly increased on d2, compared to d0. They recovered slightly on d7, and the Th1/Th2 ratio increased markedly on d7, compared with d2. In contrast, Th17, regulatory T cell (Treg), and interleukin-17 (IL-17) levels and FOXP3 mRNA expression showed no significant change on d2, and then markedly decreased on d7. Similarly, plasma IFN-γ concentration on d2 was much higher than that on d0, and then partly recovered on d7. As compared with the G group, in the G + E group, Th1 cell frequencies and the Th1/Th2 ratio were slightly higher on d2 and significantly higher on d7, while Th2, Th17, and Treg cell frequencies were slightly lower on d2, and significantly lower on d7. Consistently, on d7, IFN-γ mRNA and protein levels and the IFN-γ/IL-4 ratio in the G + E group were higher than those in the G group. In contrast, the IL-17 mRNA level, and IL-17 and transforming growth factor-β₁ concentrations in the G + E group were lower than those in the G group.
G + E is superior to G in shifting the Th1/Th2 balance towards Th1, while decreasing Th17 and Treg, potentially benefiting HCC patients by promoting anti-tumor Th polarization.
World Journal of Gastroenterology 06/2012; 18(24):3089-98. · 2.47 Impact Factor
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Fang-Ming Gu,
Qiang Gao,
Guo-Ming Shi,
Xin Zhang,
Jiping Wang,
Jia-Hao Jiang,
Xiao-Ying Wang,
Ying-Hong Shi,
Zhen-Bin Ding,
Jia Fan,
Jian Zhou
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ABSTRACT: Inflammatory reactions at a tumor site have both detrimental and beneficial effects on tumor progression. This study was designed to assess the clinical significance of tumor-infiltrating inflammatory cells in patients with intrahepatic cholangiocarcinoma (ICC).
A total of 123 consecutive ICC patients who underwent curative resection were enrolled. Tissue microarray and immunohistochemistry were used to analyze the distribution and clinical relevance of IL-17(+), FOXP3(+), CD8(+), CD66b(+) cells, and microvessel density (CD34) in different microanatomical areas.
IL-17(+) cells, FOXP3(+) lymphocytes, CD66b(+) neutrophils, and microvessels were enriched predominantly in intratumor (IT) area, whereas CD8(+) lymphocytes were most abundant in tumor invasive front. On univariate analyses, increasing IL-17 (IT) (+) and neutrophils(IT) were significantly associated with worse patient survival. Multivariate analyses revealed that IL-17 (IT) (+) (hazard ratio [HR] = 1.59; 95% confidence interval [CI], 1.05-2.41; P = 0.028), neutrophils(IT) (HR = 1.76; 95% CI, 1.16-2.65; P = 0.007), and their combination (HR 2.8; 95% CI 1.72-4.57; P < 0.001) were independent prognostic factors, which were superior to conventional clinicopathologic features, such as intrahepatic metastasis and TNM stage. IL-17 (IT) (+) significantly correlated with the presence of lymph node metastasis, intrahepatic metastasis, and advanced stages, whereas neutrophils(IT) correlated with the presence of vascular invasion. In addition, significant positive correlations were detected among densities of IL-17(+) cells, neutrophils, and microvessel density.
Our data suggested that intratumor IL-17(+) cells, neutrophils are novel, powerful predictors of prognosis in patients with ICC.
Annals of Surgical Oncology 03/2012; 19(8):2506-14. · 4.17 Impact Factor
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Quan-Lin Li, Fang-Ming Gu,
Zheng Wang,
Jia-Hao Jiang,
Li-Qing Yao,
Chang-Jun Tan,
Xiao-Yong Huang,
Ai-Wu Ke,
Zhi Dai,
Jia Fan,
Jian Zhou
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ABSTRACT: Rapamycin is an attractive approach for the treatment and prevention of HCC recurrence after liver transplantation. However, the objective response rates of rapamycin achieved with single-agent therapy were modest, supporting that rapamycin resistance is a frequently observed characteristic of many cancers. Some studies have been devoted to understanding the mechanisms of rapamycin resistance, however, the mechanisms are cell-type-dependent and studies on rapamycin resistance in HCC are extremely limited.
The anti-tumor sensitivity of rapamycin was modest in vitro and in vivo. In both human and rat HCC cells, rapamycin up-regulated the expression and phosphorylation of PDGFRβ in a time and dose-dependent manner as assessed by RT-PCR and western blot analysis. Using siRNA mediated knockdown of PDGFRβ, we confirmed that subsequent activation of AKT and ERK was PDGFRβ-dependent and compromised the anti-tumor activity of rapamycin. Then, blockade of this PDGFRβ-dependent feedback loop by sorafenib enhanced the anti-tumor sensitivity of rapamycin in vitro and in an immunocompetent orthotopic rat model of HCC.
Activation of PI3K/AKT and MAPK pathway through a PDGFRβ-dependent feedback loop compromises the anti-tumor activity of rapamycin in HCC, and blockade of this feedback loop by sorafenib is an attractive approach to improve the anti-tumor effect of rapamycin, particularly in preventing or treating HCC recurrence after liver transplantation.
PLoS ONE 01/2012; 7(3):e33379. · 4.09 Impact Factor
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Fang-Ming Gu,
Quan-Lin Li,
Qiang Gao,
Jia-Hao Jiang,
Kai Zhu,
Xiao-Yong Huang,
Jin-Feng Pan,
Jun Yan,
Jin-Hui Hu,
Zheng Wang,
Zhi Dai,
Jia Fan,
Jian Zhou
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ABSTRACT: The Th17 subset and IL-17 have been found in increased frequencies within certain tumors. However, their relevance in cancer biology remains controversial. This study aimed to clarify the biological action of IL-17 on hepatocellular carcinoma (HCC).
Effects and underlying molecular mechanisms of IL-17 on human HCC were explored in vitro using exogenous IL-17 stimulation and in nude mice by implanting IL-17 overexpressed HCC cells. The clinical significance of IL-17 was investigated in tissue microarrays containing HCC tissues from 323 patients following hepatectomy using immunohistochemistry.
Although exogenous IL-17 showed no direct effect on the growth rate of HCC cells in vitro, PCR and ELISA showed that IL-17 selectively augmented the secretion of diverse proinvasive factors and transwell showed a direct promotion of invasion of HCC cells by IL-17. Furthermore, transfection of IL-17 into HCC cells significantly promoted neoangiogenesis, neutrophil recruitment and tumor growth in vivo. Using siRNA mediated knockdown of AKT and STAT3, we suggested that the effects of IL-17 were operated through activation of the AKT signaling in HCC, which resulted in IL-6 production. Then, IL-6 in turn activated JAK2/STAT3 signaling and subsequently up-regulated its downstream targets IL-8, MMP2, and VEGF. Supporting these findings, in human HCC tissues, immunostaining indicated that IL-17 expression was significantly and positively associated with STAT3 phosphorylation, neutrophil infiltration and increased tumor vascularity. The clinical significance of IL-17 was authenticated by revealing that the combination of intratumoral IL-17+ cells and phospho-STAT3 served as a better prognosticator for postoperative tumor recurrence than either marker alone.
IL-17 mediated tumor-promoting role involves a direct effect on HCC cells through IL-6/JAK2/STAT3 induction by activating the AKT pathway.
Molecular Cancer 12/2011; 10:150. · 3.99 Impact Factor
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ABSTRACT: To investigate the inhibitory role and the underlying mechanisms of sorafenib on signal transducer and activator of transcription 3 (STAT3) activity in hepatocellular carcinoma (HCC).
Human and rat HCC cell lines were treated with sorafenib. Proliferation and STAT3 dephosphorylation were assessed. Potential molecular mechanisms of STAT3 pathway inhibition by sorafenib were evaluated. In vivo antitumor action and STAT3 inhibition were investigated in an immunocompetent orthotopic rat HCC model.
Sorafenib decreased STAT3 phosphorylation at the tyrosine and serine residues (Y705 and S727), but did not affect Janus kinase 2 (JAK2) and phospha-tase shatterproof 2 (SHP2), which is associated with growth inhibition in HCC cells. Dephosphorylation of S727 was associated with attenuated extracellular signal-regulated kinase (ERK) phosphorylation, similar to the effects of a mitogen-activated protein kinase (MEK) inhibitor U0126, suggesting that sorafenib induced S727 dephosphorylation by inhibiting MEK/ERK signaling. Meanwhile, sorafenib could also inhibit Akt phosphorylation, and both the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and Akt knockdown resulted in Y705 dephosphorylation, indicating that Y705 dephosphorylation by sorafenib was mediated by inhibiting the PI3K/Akt pathway. Finally, in the rat HCC model, sorafenib significantly inhibited STAT3 activity, reducing tumor growth and metastasis.
Sorafenib inhibits growth and metastasis of HCC in part by blocking the MEK/ERK/STAT3 and PI3K/Akt/STAT3 signaling pathways, but independent of JAK2 and SHP2 activation.
World Journal of Gastroenterology 09/2011; 17(34):3922-32. · 2.47 Impact Factor
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ABSTRACT: Previous studies have indicated that CD151, a hydrophobic protein, forms a functional complex with the proto-oncogene that encodes an N-methyl-N'-nitro-N-nitroso-guanidine (MET) protein (c-Met), and CD151 overexpression reportedly is involved in metastasis/invasion of several tumors. The objective of the current study was to investigate the expression and role of CD151 and/or c-Met in intrahepatic cholangiocarcinoma (ICC).
Sixty ICC tissues with matched nontumorous tissues and 20 normal liver tissues were used to analyze CD151 expression at the level of messenger RNA (mRNA) and protein. Then, the expression of CD151 in an ICC cell line was interrupted using a specific lentiviral-mediated small hairpin RNA (shRNA)-CD151, and the role of CD151 in the proliferation, metastasis, and invasion of ICC cells was assessed. The expression of CD151/c-Met was examined further by immunohistochemistry in a tissue microarray (TMA) that included 140 samples of ICC, and the prognostic role of CD151 and/or c-Met in ICC was evaluated in Kaplan-Meier and Cox regression analyses.
The expression of CD151 in ICC tissues was much higher than that in nontumorous samples and normal liver; and, after the down-regulation of CD151, HCCC-9810 cells had decreased capability for metastasis/invasion in vitro. CD151 overexpression was correlated significantly with larger tumors, poor differentiation, multiple nodular, microvascular/bile duct invasion, and lymphatic metastasis (P<.05). The postoperative 2-year and 5-year overall survival (OS) rates for patients with low CD151 expression (<50% tumor staining) and/or low c-Met expression (<20% tumor staining) were higher than the rates for patients with high CD151 expression (≥50% tumor staining) and/or high c-Met expression (≥20% tumor staining). Multivariate analysis revealed that CD151 overexpression and c-Met overexpression were independent prognostic markers for ICC.
Overexpression of CD151 was implicated in metastasis/invasion of ICC, and both CD151 overexpression and c-Met overexpression may be potential molecular therapeutic targets for ICC.
Cancer 12/2010; 116(23):5440-51. · 4.77 Impact Factor
