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ABSTRACT: CXCL5 (epithelial neutrophil-activating peptide-78) is a member of a proangiogenic subgroup of the CXC-type chemokine family of small, secreted proteins. Recently, evidence that CXCL5 is involved in carcinogenesis and cancer progression has emerged. To investigate the role of CXCL5 in tumor growth, invasion, and prognosis of hepatocellular carcinoma (HCC), we examined CXCL5 mRNA and protein levels in HCC cell lines with various metastatic potentials and in three independent cohorts of 919 HCC patients. We found that CXCL5 expression was increased in the highly metastatic HCC cell lines and in tumor tissues from patients with recurrent HCC compared to controls. CXCL5 activated the PI3K-Akt and ERK1/2 signaling pathways in HCC cells and promoted proliferation, migration, and invasion. Furthermore, we found that CXCL5 had a direct chemoattractant effect on neutrophils in vitro. In animal studies, the up-regulation of CXCL5 in HCC cells promoted tumor growth, lung metastasis, and intratumoral neutrophil infiltration. Conversely, down-regulation of CXCL5 in HCC cells reduced tumor growth, metastasis, and intratumoral neutrophil infiltration. Immunohistochemical analysis in HCC samples showed that overexpression of CXCL5 was well correlated with intratumoral neutrophil infiltration, shorter overall survival, and tumor recurrence. Multivariate analysis revealed that CXCL5 overexpression alone, or combined with the presence of intratumoral neutrophils, was an independent prognostic indicator for overall survival and cumulative recurrence. CONCLUSION: CXCL5 promotes HCC cell proliferation, invasion, and intratumoral neutrophil infiltration. CXCL5 overexpression, alone or combined with intratumoral neutrophil presence, is a novel prognostic predictor, and CXCL5 is a potential therapeutic target for HCC. (HEPATOLOGY 2012.).
Hepatology 06/2012; · 11.66 Impact Factor
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Kai Zhu,
Zhi Dai,
Qi Pan,
Zheng Wang, Guo-Huan Yang,
Lei Yu,
Zhen-Bin Ding,
Guo-Ming Shi,
Ai-Wu Ke,
Xin-Rong Yang,
Zhong-Hua Tao,
Yi-Ming Zhao,
Yi Qin,
Hai-Ying Zeng,
Zhao-You Tang,
Jia Fan,
Jian Zhou
[show abstract]
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ABSTRACT: To investigate the expression of metadherin (MTDH) for its prognostic value in hepatocellular carcinoma (HCC) and its role in promoting HCC metastasis.
This study employed a tissue microarray containing samples from 323 HCC patients to examine the expression of MTDH and its correlation with other clinicopathologic characteristics. The role of MTDH in the regulation of HCC metastasis was investigated both in vitro and in vivo using short hairpin RNA (shRNA)-mediated downregulation of MTDH in HCC cell lines with various metastatic potentials.
The expression of MTDH was markedly higher in HCC tumors than in normal liver tissue. Particularly high MTDH expression was observed in tumors with microvascular invasion, pathologic satellites, poor differentiation, or tumor-node-metastasis stages II to III. Furthermore, the clinical outcome was consistently poorer for the MTDH(high) group than for the MTDH(low) group in the 1-, 3-, and 5-year overall survival (OS) rates and in the 1-, 3-, 5-year cumulative recurrence rates. In a nude mice model, the shRNA-mediated downregulation of MTDH resulted in a reduced migratory capacity in HCC cell lines, as well as a reduction in pulmonary and abdominal metastasis. Furthermore, we found that the expression level of MTDH correlated with four epithelial-mesenchymal transition (EMT) markers. Knockdown of MTDH expression in HCC cell lines resulted in downregulation of N-cadherin and snail, upregulation of E-cadherin, and translocation of β-catenin.
MTDH may promote HCC metastasis through the induction of EMT process and may be a candidate biomarker for prognosis as well as a target for therapy.
Clinical Cancer Research 12/2011; 17(23):7294-302. · 7.74 Impact Factor
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Jie Hu,
Zheng Wang,
Jia Fan,
Zhi Dai,
Yi-Feng He,
Shuang-Jian Qiu,
Xiao-Wu Huang,
Jian Sun,
Yong-Sheng Xiao,
Kang Song,
Ying-Hong Shi,
Qi-Man Sun,
Xin-Rong Yang,
Guo-Ming Shi,
Lei Yu, Guo-Huan Yang,
Zhen-Bin Ding,
Qiang Gao,
Zhao-You Tang,
Jian Zhou
[show abstract]
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ABSTRACT: Recurrence prediction of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) present a great challenge because of a lack of biomarkers. Genetic variations play an important role in tumor development and metastasis.
Oligonucleotide microarrays were used to evaluate the genetic characteristics of tumor DNA in 30 HBV-related HCC patients who were underwent LT. Recurrence-related single-nucleotide polymorphism were selected, and their prognostic value was assessed and validated in two independent cohorts of HCC patients (N = 102 and N = 77), using pretransplant plasma circulating DNA. Prognostic significance was assessed by Kaplan-Meier survival estimates and log-rank tests. Multivariate analyses were performed to evaluate prognosis-related factors.
rs894151 and rs12438080 were significantly associated with recurrence (P = .003 and P = .004, respectively). Multivariate analyses demonstrated that the co-index of the 2 SNPs was an independent prognostic factor for recurrence (P = .040). Similar results were obtained in the third cohort (N = 77). Furthermore, for HCC patients (all the 3 cohorts) exceeding Milan criteria, the co-index was a prognostic factor for recurrence and survival (P<.001 and P = .002, respectively).
Our study demonstrated first that genetic variations of rs894151 and rs12438080 in pretransplant plasma circulating DNA are promising prognostic markers for tumor recurrence in HCC patients undergoing LT and identify a subgroup of patients who, despite having HCC exceeding Milan criteria, have a low risk of post-transplant recurrence.
PLoS ONE 01/2011; 6(10):e26003. · 4.09 Impact Factor
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Guo-Ming Shi,
Ai-Wu Ke,
Jian Zhou,
Xiao-Ying Wang,
Yang Xu,
Zhen-Bin Ding,
Ranjan Prasad Devbhandari,
Xiao-Yong Huang,
Shuang-Jian Qiu,
Ying-Hong Shi,
Zhi Dai,
Xin-Rong Yang, Guo-Huan Yang,
Jia Fan
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ABSTRACT: Tetraspanin CD151 is involved in several pathological activities associated with tumor progression, including neoangiogenesis. However, the role and molecular mechanism of CD151 in the neoangiogenesis of hepatocellular carcinoma (HCC) remain enigmatic. We found that the level of expression of matrix metalloproteinase 9 (MMP9) was positively associated with CD151 expression in HCC cells. We developed a zone-by-zone blockade and demonstrated that overexpression of CD151 in HCC cells facilitated MMP9 expression through a phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3beta (GSK-3beta)/Snail signaling pathway. In contrast, down-regulation of CD151 expression impaired the ability of HCC cells to form microvessels in vitro and reduced their in vivo metastatic potential. In a clinical setting, a significant correlation of the expression of CD151 with MMP9 expression and with microvessel density (MVD) was revealed by Pearson correlation analysis of HCC patients. The postoperative 3-, 5-, and 7-year overall survival rates of HCC patients with CD151(high)/MMP9(high)/MVD(high) were significantly lower than those of the CD151(low)/MMP9(low)/MVD(low) group or groups in which only one or two of CD151, MMP9, and MVD were highly expressed. Cumulative recurrence rates were also highest in HCC patients with CD151(high)/MMP9(high)/MVD(high) in comparison with the other groups. Multivariate Cox proportional hazards analysis showed that the concomitant overexpression of CD151, MMP9, and MVD was an independent marker for predicting poor prognosis of HCC. CONCLUSION: Overexpression of CD151 up-regulated the expression of MMP9 through the PI3K/Akt/GSK-3beta/Snail pathway. CD151-dependent neoangiogenesis appeared to promote the progression of HCC, and this suggests that CD151 may be useful as a high-priority therapeutic target for antiangiogenesis in HCC.
Hepatology 07/2010; 52(1):183-96. · 11.66 Impact Factor
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Xin-Rong Yang,
Yang Xu,
Bin Yu,
Jian Zhou,
Shuang-Jian Qiu,
Guo-Ming Shi,
Bo-Heng Zhang,
Wei-Zhong Wu,
Ying-Hong Shi,
Bin Wu, Guo-Huan Yang,
Yuan Ji,
Jia Fan
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ABSTRACT: To investigate the prognostic values of putative hepatic stem/progenitor cell (HSC/HPC) biomarkers in patients with hepatocellular carcinoma (HCC).
Fourteen biomarkers related to HSCs/HPCs or tumour angiogenesis were assessed by qRT-PCR and then validated by tissue microarrays (TMAs) in three independent cohorts of patients with HCC undergoing curative resection (n=67, 314 and 73).
Most of the biomarkers were found to be overexpressed in patients with recurrent HCC by quantitative reverse transcription-PCR (qRT-PCR). The HSC/HPC biomarkers cytokeratin 19, ATP-binding cassette subfamily G member 2 (ABCG2), CD133, Nestin and CD44, and the markers of angiogenesis microvessel density (MVD, determined by CD34 immunostaining), vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) were confirmed as significant predictors for overall survival (OS) and/or relapse-free survival (RFS) in TMA analysis. As compared with the low HSC/HPC profile group, patients with a high HSC/HPC profile who had higher VEGF levels (p=0.012) and MVD (p=0.030) in tumours had significantly lower OS and RFS (p<0.0001). Based on Cox regression, a simplified model including CD133, CD44, Nestin and MVD was constructed and confirmed as an independent predictor for OS (p<0.0001) and RFS (p<0.0001), regardless of alpha-fetoprotein level, tumour stage and recurrence time (p<0.0001 for all).
High expression levels of HSC/HPC biomarkers are related to tumour angiogenesis and poor prognosis of HCC. The simplified model based on the HSC/HPC and tumour angiogenesis profile can be used to classify patients with HCC with a high risk of tumour recurrence after surgery.
Gut 05/2010; 59(7):953-62. · 10.11 Impact Factor
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Xin-Rong Yang,
Yang Xu,
Bin Yu,
Jian Zhou,
Jia-Chu Li,
Shuang-Jian Qiu,
Ying-Hong Shi,
Xiao-Ying Wang,
Zhi Dai,
Guo-Ming Shi,
Bin Wu,
Li-Ming Wu, Guo-Huan Yang,
Bo-Heng Zhang,
Wen-Xin Qin,
Jia Fan
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ABSTRACT: To investigate the role of CD24 in tumor invasion and prognostic significance in hepatocellular carcinoma (HCC).
CD24 expression was measured in stepwise metastatic HCC cell lines, tumor, peritumoral tissues, and normal liver tissues by quantitative real-time PCR and Western blot. The role of CD24 in HCC was investigated by CD24 depletion using small interfering RNA. Tumor tissue microarrays of 314 HCC patients who underwent resection between 1997 and 2000 were used to detect expression of CD24, beta-catenin, and proliferating cell nuclear antigen. Prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests.
CD24 was overexpressed in the highly metastatic HCC cell line and in tumor tissues of patients with recurrent HCC. Depletion of CD24 caused a notable decrease in cell proliferation, migration, and invasiveness in vitro. Univariate and multivariate analyses revealed that CD24 was a significant predictor for overall survival and relapse-free survival. CD24 expression was correlated with poor prognosis independent of alpha-fetoprotein, tumor-node-metastasis stage, and Edmondson stage. High CD24 expression was significantly associated with cytoplasmic and nuclear accumulation of beta-catenin (P = 0.023), high tumor proliferative status (P = 0.018), and diffused intrahepatic recurrence and distant metastasis (P = 0.026). Adjuvant transcatheter arterial chemoembolization after surgery reduced the rate of early recurrence (<or=1 year) in CD24(+) HCC patients (P = 0.024) but had no significant effect in CD24(-) patients (P = 0.284).
Overexpression of CD24 in HCC was associated with high invasiveness and metastatic potential, high tumor proliferation status, and activation of the Wnt/beta-catenin pathway. CD24 may be a novel predictor for poor prognosis of HCC patients after surgery.
Clinical Cancer Research 09/2009; 15(17):5518-27. · 7.74 Impact Factor
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Journal of Cancer Research and Clinical Oncology 09/2009; · 2.56 Impact Factor
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Guo-Huan Yang,
Jia Fan,
Yang Xu,
Shuang-Jian Qiu,
Xin-Rong Yang,
Guo-Ming Shi,
Bing Wu,
Zhi Dai,
Yin-Kun Liu,
Zhao-You Tang,
Jian Zhou
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ABSTRACT: Osteopontin (OPN) plays important roles in tumor progression and metastasis through binding to CD44 and integrin. The goal of this study was to elucidate the prognostic significance of OPN and CD44 in hepatocellular carcinoma patients.
Tumor tissue microarray was used to detect the expression levels of OPN and CD44 in 302 hepatocellular carcinoma patients undergoing curative resection between 1997 and 2000 at our institute. Clinicopathologic data for these patients were investigated. The prognostic effects of OPN and CD44 were evaluated using the Kaplan-Meier method and compared using the log-rank test. The Spearman rank test and Fisher's exact test were applied to demonstrate correlations.
Both OPN and CD44 were independent predictors for overall survival and disease-free survival. When OPN and CD44 were taken into consideration together, the predictive range was extended and the sensitivity was improved, especially for those patients with normal serum alpha-fetoprotein levels. The 8-year overall survival and disease-free survival rates in OPN+ and/or CD44+ patients were 28.2% and 25.6%, respectively, which were significantly lower than those of OPN-CD44- patients (52.1% and 51.6%, respectively).
OPN combined with CD44 is a promising independent predictor of tumor recurrence and survival in hepatocellular carcinoma patients.
The Oncologist 12/2008; 13(11):1155-65. · 3.91 Impact Factor
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Guo-Ming Shi,
Yang Xu,
Jia Fan,
Jian Zhou,
Xin-Rong Yang,
Shuang-Jian Qiu,
Yong Liao,
Wei-Zhong Wu,
Yuan Ji,
Ai-Wu Ke,
Zhen-Bin Ding,
Yi-Zhou He,
Bing Wu, Guo-Huan Yang,
Wen-Zhen Qin,
Wu Zhang,
Jiang Zhu,
Zhi-Hui Min,
Zhi-Quan Wu
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ABSTRACT: To identify the side population (SP) cells from four hepatocellular carcinoma (HCC) cell lines with stepwise metastatic potentials.
SP cells were sorted from HCCLM3, MHCC97-H, MHCC97-L and Hep3B by flow cytometry, and then analyzed by differentiation study, clonogenic assay, chemoresistance study and tumorigenicity assay in vivo. The expression of ABCG(2) in SP cells was detected by immunocytochemistry, western blotting and real-time quantitative PCR, respectively.
There was significant difference in SP proportion among HCCLM3, MHCC97-H, MHCC97-L and Hep3B (28.7 +/- 1.6%, 14.5 +/- 0.6%, 4.2 +/- 0.4%, 0.9 +/- 0.1%, respectively, P < 0.01). All the SP cells showed similar characteristics of self-renewal, high clonogenicity, remarkable chemo-resistance and high expression of ABCG(2). As low as 2,000 SP cells could initiate tumors in non-obese diabetic/severe combined immunodeficiency mice successfully.
SP cells purified from HCC cell lines harbors cancer stem cell-like properties, and may be related to the metastatic potentials and therapeutic-resistance of HCC.
Journal of Cancer Research and Clinical Oncology 06/2008; 134(11):1155-63. · 2.56 Impact Factor
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Xin-Rong Yang,
Yang Xu,
Guo-Ming Shi,
Jia Fan,
Jian Zhou,
Yuan Ji,
Hui-Chuan Sun,
Shuang-Jian Qiu,
Bing Yu,
Qiang Gao,
Yi-Zhou He,
Weng-Zhen Qin,
Rong-Xin Chen, Guo-Huan Yang,
Bing Wu,
Qing Lu,
Zhi-Quan Wu,
Zhao-You Tang
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ABSTRACT: Cytokeratin 10 (CK10) was found to be expressed differently in human hepatocellular carcinoma (HCC) cell lines with different metastatic potentials in our previous research. The aim of this study was to assess the value of CK10 alone or in combination with cytokeratin 19 (CK19) in predicting tumor recurrence after curative resection in HCC patients.
CK10 expression in stepwise metastatic HCC cell lines and tumor tissues from 50 HCC patients was investigated using immunofluorescence assay, quantitative real-time reverse transcription-PCR, and Western blot analyses. Tumor tissue microarrays of 300 HCC patients who underwent curative resection between 1997 and 2000 were used to detect the expressions of CK10 and CK19. Clinicopathologic data for these patients were evaluated. The prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests.
CK10 was overexpressed in the high metastatic HCC cell line and in tumor tissues of recurrent patients. Both univariate and multivariate analyses revealed that CK10 was a significant predictor for overall survival (OS) and disease-free survival, and that CK19 was a significant predictor for OS. CK10 expression was correlated with poor prognosis regardless of alpha-fetoprotein, tumor-node-metastasis stage, and vascular invasion. The 7-year OS and disease-free survival rates in CK10+ and/or CK19+ patients were 30.0% and 37.6%, respectively, which were significantly lower than that of CK10-/CK19- patients (56.1% and 60.0%, respectively; P < 0.001).
CK10 is associated with HCC invasiveness. CK10 alone, or in combination with CK19, can be a novel predictor for poor prognosis of HCC patients after curative resection.
Clinical Cancer Research 06/2008; 14(12):3850-9. · 7.74 Impact Factor
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Yi-feng He,
Jia Fan,
Jian Zhou,
Zhi-quan Wu,
Shuang-jian Qiu,
Xiao-wu Huang,
Yao Yu,
Jian Sun,
Yong-sheng Xiao, Guo-huan Yang,
Kang Song,
Zheng Wang,
Zhao-you Tang,
Yu-qi Wang
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ABSTRACT: To analyze the risk factors influencing the prognosis of orthotopic liver transplantation for hepatocellular carcinoma (HCC) and sum up the relevant clinical experience in diagnosis and treatment of HCC.
The clinical data of 198 HCC patients, 177 males and 21 females, aged 49 (24-83), were analyzed.
The 0.5-, 1-, and 2-year survival rates were 89%, 78%, and 65 respectively. The rates of disease-free survival (DFS) were 85%, 73, and 67% respectively. Univariate analysis revealed that tumor size, presence of vascular invasion, Edmondson grade, TNM classification, and preoperative alpha-fetoprotein (AFP) were significantly related to DFS, and the 4 foregoing factors were also related to the survival rate. Cox regression analysis suggested that presence of vascular invasion was an independent prognostic factor of survival rate and DFS.
Vascular invasion plays a leading role in evaluating the prognosis of orthotopic liver transplantation for HCC. It is important to discover the micro-metastasis and explore more effective approaches to prevent recurrence after transplantation.
Zhonghua yi xue za zhi 06/2006; 86(18):1232-5.
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Jian Zhou,
Jia Fan,
Zhi-quan Wu,
Shuang-jian Qiu,
Xiao-wu Huang,
Yao Yu,
Zheng Wang,
Jian Sun,
Yong-sheng Xiao,
Yi-feng He, Guo-huan Yang,
Kang Song,
Zhou Yuan,
Yu-qi Wang,
Zhao-you Tang
[show abstract]
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ABSTRACT: Selection of patients with hepatocellular carcinoma (HCC) for orthotopic liver transplantation (OLT) remains controversial. Since there is a trend to expand the transplant criteria for HCC patients, we reviewed the data of patients with HCC who had received OLT at our institute to determine their survival and prognostic factors.
A total of 67 patients with HCC who had undergone OLT from April 2001 through December 2003 were reviewed retrospectively. Selection OLT candidates with HCC was dependent on the anatomical characteristics and/or the severity of underlying liver cirrhosis. The 67 patients were followed up for more than 6 months after transplantation. Their survival rate was calculated by the Kaplan-Meier method. Univariate and multivariate analyses using the Cox proportional hazards regression model were performed to reveal the factors affecting the survival rate.
No perioperative death occurred in this series. The 1- and 2-year cumulative survival rates were 90.0% and 65.6%, and the disease-free survival (DFS) rates were 77.5% and 62.5% respectively. Univariate analysis revealed the tumor size, portal vein tumor thrombus (PVTT), serum alpha-fetoprotein level, bilobular distribution of tumors, pTNM stage and histological differentiation were statistically significant factors affecting the DFS (P < 0.05). Multivariate analysis showed tumor size and PVTT were independent and statistically significant factors affecting the DFS (P = 0.005 and 0.010, respectively). In this series, all but 2 received systemic chemotherapy, among them 13 had tumor recurrence within 8 months after OLT.
OLT is indicated for patients with HCC, even for some patients with end-stage liver disease who may survive longer without tumor recurrence. Adjuvant chemotherapy may decrease the recurrence of HCC after OLT.
Chinese medical journal 04/2005; 118(8):654-9. · 0.86 Impact Factor
