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Xiao-Yong Huang,
Ai-Wu Ke,
Guo-Ming Shi,
Xin Zhang,
Chi Zhang,
Ying-Hong Shi, Xiao-Ying Wang,
Zhen-Bin Ding,
Yong-Sheng Xiao,
Jun Yan,
Shuang-Jian Qiu,
Jia Fan,
Jian Zhou
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ABSTRACT: The overall survival of patients with hepatocellular carcinoma (HCC) remains poor, and the molecular pathogenesis remains incompletely defined in HCC. Here, we report that increased expression of αB-Crystallin in human HCC predicts poor survival and disease recurrence after surgery. Multivariate analysis identifies αB-Crystallin expression as an independent predictor for postoperative recurrence and overall survival. We unveil that elevated expression of αB-Crystallin promotes HCC progression in vivo and in vitro. We demonstrate that αB-Crystallin overexpression fosters HCC progression by inducing epithelial-mesenchymal transition (EMT) in HCC cells through activation of the ERK cascade, which can counteract the effect of sorafenib. αB-Crystallin complexes with and elevates 14-3-3ζ protein, leading to up-regulation of ERK1/2 activity. Moreover, overexpression of αB-Crystallin in HCC cells induces EMT progression through an ERK1/2/Fra-1/slug signaling pathway. Clinically, our data reveal that overexpression of both αB-Crystallin and 14-3-3ζ correlates with the HCC poorest survival outcomes, and sorafenib response is impaired in patients with αB-Crystallin overexpression. Conclusions: These data suggest that the αB-Crystallin-14-3-3ζ complex acts synergistically to promote HCC progression by constitutively activating ERK signaling. This study reveals αB-Crystallin as a potential therapeutic target for HCC and a biomarker for predicting sorafenib treatment response. (HEPATOLOGY 2013.).
Hepatology 01/2013; · 11.66 Impact Factor
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Zhi-Chao Wang,
Qiang Gao,
Jie-Yi Shi,
Liu-Xiao Yang,
Jian Zhou, Xiao-Ying Wang,
Ying-Hong Shi,
Ai-Wu Ke,
Guo-Ming Shi,
Zhen-Bin Ding,
Zhi Dai,
Shuang-Jian Qiu,
Jia Fan
[show abstract]
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ABSTRACT: BACKGROUND: Frequent deletions of the kinesin-like protein gene 1B (KIF1B) have been reported in neural tumors. Recently, a genome-wide association study revealed an association between polymorphisms in the KIF1B gene and the risk of hepatocellular carcinoma (HCC), and several case-control studies have further investigated this relationship. However, these studies have yielded controversial results. We therefore performed a meta-analysis to derive a more precise estimation of the association between the KIF1B gene polymorphisms and HCC risk. METHODOLOGYPRINCIPAL FINDING: PubMed, EMBASE, the ISI Web of Science and the CNKI databases were systematically searched to identify relevant studies. A total of 5 studies containing 13 cohorts with 5,773 cases and 6,404 controls were included. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to assess the strength of the associations. Subgroup analyses were conducted based on ethnicities, sample sizes and quality scores. Overall, the G allele at rs17401966 of the KIF1B gene was associated with a significantly decreased risk for HCC (OR = 0.81, 95%CI: 0.70-0.93; P = 0.003). Furthermore, subgroup analyses showed that the G allele at rs17401966 of the KIF1B gene significantly reduced the risk for HCC in Chinese cohorts (OR = 0.76, 95%CI: 0.64-0.90; P = 0.002), large-sample-size cohorts (OR = 0.80, 95%CI: 0.73-0.88, P<0.01) and high-quality cohorts (OR = 0.78, 95%CI: 0.71-0.87, P<0.01). However, no significant associations were found in small-sample-size cohorts, studies with low-quality scores and when excluding the cohorts from the study reporting the original discovery. CONCLUSIONSIGNIFICANCE: These findings demonstrate that the presence of the G allele at rs17401966 of the KIF1B gene may decrease the risk for HCC and suggest that KIF1B may play a critical role in the development of HCC. High-quality studies with larger sample sizes and different ethnic populations will be of great value to further confirm these findings.
PLoS ONE 01/2013; 8(4):e62571. · 4.09 Impact Factor
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Qiang Gao,
Ying-Jun Zhao, Xiao-Ying Wang,
Shuang-Jian Qiu,
Ying-Hong Shi,
Jian Sun,
Yong Yi,
Jie-Yi Shi,
Guo-Ming Shi,
Zhen-Bin Ding,
Yong-Sheng Xiao,
Zhong-Hua Zhao,
Jian Zhou,
Xiang-Huo He,
Jia Fan
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ABSTRACT: CXC chemokines and their cognate receptors have been implicated widely in cancer pathogenesis. In this study, we report a critical causal relationship between CXCR6 expression and tumorigenesis in the setting of human hepatocellular carcinoma (HCC). Among the CXC chemokine receptors, only CXCR6 was detected in all the hepatoma cell lines studied. Moreover, in HCC tissue, CXCR6 expression was significantly higher than in noncancerous liver tissues. Reduction of CXCR6 or its ligand CXCL16 in cancer cells reduced cell invasion in vitro and tumor growth, angiogenesis, and metastases in vivo. Importantly, loss of CXCR6 led to reduced Gr-1+ neutrophil infiltration and decreased neoangiogenesis in hepatoma xenografts via inhibition of proinflammatory cytokine production. Clinically, high expression of CXCR6 was an independent predictor of increased recurrence and poor survival in HCCs. Human HCC samples expressing high levels of CXCR6 also contained an increased number of CD66b+ neutrophils and microvessels, and the combination of CXCR6 and neutrophils was a superior predictor of recurrence and survival than either marker used alone. Together, our findings suggest that elevated expression of CXCR6 promotes HCC invasiveness and a protumor inflammatory environment and is associated with poor patient outcome. These results support the concept that inhibition of the CXCR6-CXCL16 pathway may improve prognosis after HCC treatment.
Cancer Research 06/2012; 72(14):3546-56. · 7.86 Impact Factor
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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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Tai-Wei Sun,
Qiang Gao,
Shuang-Jian Qiu,
Jian Zhou, Xiao-Ying Wang,
Yong Yi,
Jie-Yi Shi,
Yong-Feng Xu,
Ying-Hong Shi,
Kang Song,
Yong-Sheng Xiao,
Jia Fan
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ABSTRACT: B7-H3, a novel B7 family member, positively or negatively regulates T-cell responses. We investigated the clinical relevance and prognostic significance of B7-H3 in hepatocellular carcinoma (HCC). Western blotting showed B7-H3 upregulation in 17 of 24 (70.8 %) HCC tissues compared with nontumor liver tissues (p = 0.028). B7-H3 immunostaining on tissue microarrays containing 240 HCC patient samples indicated that 225 (93.8 %) tumors had aberrant B7-H3 expression, with strong intensity in 79 (32.9 %) cases, whereas B7-H3 expression in peritumor liver cells was weak in most cases (226; 94.2 %). Notably, patients with high/moderate tumor cell B7-H3 expression showed significantly poorer survival (p = 0.009) and increased recurrence (p = 0.002). After multivariable adjustment, high/moderate B7-H3 expression remained significant for an increased risk of recurrence (hazard ratio = 1.79; 95 % confidence interval = 1.19-2.70; p = 0.005). B7-H3 expression correlated with invasive phenotypes like vascular invasion and advanced tumor stage, and the metastatic potential of HCC cell lines. Flow cytometry showed that B7-H3 expression is inversely correlated with proliferation and interferon-γ production by infiltrating T cells. Interferon-γ stimulation significantly upregulated B7-H3 expression in HCC cells in vitro, implicating B7-H3 expression as a feedback mechanism to evade anti-tumor immunity. Importantly, the prognostic value of B7-H3 expression was validated in an independent cohort of 206 HCC patients. Collectively, our data suggest that B7-H3 was abundantly expressed in HCC and was associated with adverse clinicopathologic features and poor outcome. Thus, B7-H3 represents an attractive target for diagnostic and therapeutic manipulation in human HCC.
Cancer Immunology and Immunotherapy 05/2012; · 3.70 Impact Factor
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ABSTRACT: In vitro experiments and mice models have confirmed the importance of Sprouty 2 (Spry2) in inhibiting tumorigenesis and the progression of human cancer. However, the prognostic value of Spry2 in cancer patients remains unknown. This study is aimed to investigate the clinical relevance and prognostic significance of Spry2 expression in patients with hepatocellular carcinoma (HCC).
With samples from 240 randomly-selected HCC patients who underwent surgery, immunohistochemistry was used to investigate Spry2 expression on tissue microarrays. The correlation of Spry2 expression with survival was estimated by the Kaplan-Meier method and univariate/multivariate Cox proportional hazard regression analysis. Spry2, ERK and phospho-ERK expression in HCC cell lines was detected by Western blotting.
Among the patients, 86.3% (207 of 240) exhibited down-regulation of Spry2 expression. Patients negative for Spry2 showed poorer survival (P=0.002) and increased recurrence (P=0.003). Multivariate analysis further established Spry2 as an independent predictor of postoperative recurrence in HCC patients (HR=1.47; 95% CI, 1.02-2.08; P=0.037). Down-regulation of Spry2 was associated with highly malignant phenotypes like vascular invasion and advanced tumor stages, and was positively correlated with the metastatic potential of HCC cell lines.
In the era of molecular targeted therapy, the expression of Spry2 in HCC may have relevant clinical significance and turn out to be a key factor in prognostic assessment and in treatment planning.
Hepatobiliary & pancreatic diseases international: HBPD INT 04/2012; 11(2):177-84. · 1.08 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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Xiao-Yong Huang,
Guo-Ming Shi,
Ranjan Prasad Devbhandari,
Ai-Wu Ke,
Yuwei Wang, Xiao-Ying Wang,
Zheng Wang,
Ying-Hong Shi,
Yong-Sheng Xiao,
Zhen-Bin Ding,
Zhi Dai,
Yang Xu,
Wei-Ping Jia,
Zhao-You Tang,
Jia Fan,
Jian Zhou
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ABSTRACT: Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor involved in receptor-mediated endocytosis and cell signaling. The aim of this study was to elucidate the expression and mechanism of LRP1 in hepatocellular carcinoma (HCC).
LRP1 expression in 4 HCC cell lines and 40 HCC samples was detected. After interruption of LRP1 expression in a HCC cell line either with specific lentiviral-mediated shRNA LRP1 or in the presence of the LRP1-specific chaperone, receptor-associated protein (RAP), the role of LRP1 in the migration and invasion of HCC cells was assessed in vivo and in vitro, and the expression of matrix metalloproteinase (MMP) 9 in cells and the bioactivity of MMP9 in the supernatant were assayed. The expression and prognostic value of LRP1 were investigated in 327 HCC specimens.
Low LRP1 expression was associated with poor HCC prognosis, with low expression independently related to shortened overall survival and increased tumor recurrence rate. Expression of LRP1 in non-recurrent HCC samples was significantly higher than that in early recurrent samples. LRP1 expression in HCC cell lines was inversely correlated with their metastatic potential. After inhibition of LRP1, low-metastatic SMCC-7721 cells showed enhanced migration and invasion and increased expression and bioactivity of MMP9. Correlation analysis showed a negative correlation between LRP1 and MMP9 expression in HCC patients. The prognostic value of LRP1 expression was validated in the independent data set.
LRP1 modulated the level of MMP9 and low level of LRP1 expression was associated with aggressiveness and invasiveness in HCCs. LRP1 offered a possible strategy for tumor molecular therapy.
PLoS ONE 01/2012; 7(3):e32775. · 4.09 Impact Factor
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Ying-Hong Shi,
Zhen-Bin Ding,
Jian Zhou,
Bo Hui,
Guo-Ming Shi,
Ai-Wu Ke, Xiao-Ying Wang,
Zhi Dai,
Yuan-Fei Peng,
Cheng-Yu Gu,
Shuang-Jian Qiu,
Jia Fan
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ABSTRACT: Sorafenib, a potent multikinase inhibitor, has been recognized as the standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). However, the direct functional mechanism of tumor lethality mediated by sorafenib remains to be fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, we showed sorafenib induced both apoptosis and autophagy in human HCC cells through a mechanism that involved endoplasmic reticulum (ER) stress and was independent of the MEK1/2-ERK1/2 pathway. Upregulation of IRE1 signals from sorafenib-induced ER stress was critical for the induction of autophagy. Moreover, autophagy activation alleviated the ER stress-induced cell death. Inhibition of autophagy using either pharmacological inhibitors or essential autophagy gene knockdown enhanced cell death in sorafenib treated HCC cell lines. Critically, the combination of sorafenib with the autophagy inhibitor chloroquine produced more pronounced tumor suppression in HCC both in vivo and in vitro. These findings indicated that both ER stress and autophagy were involved in the cell death evoked by sorafenib in HCC cells. The combination of autophagy modulation and molecular targeted therapy is a promising therapeutic strategy in treatment of HCC.
Autophagy 10/2011; 7(10):1159-72. · 7.45 Impact Factor
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Zhen-Bin Ding,
Bo Hui,
Ying-Hong Shi,
Jian Zhou,
Yuan-Fei Peng,
Cheng-Yu Gu,
Hua Yang,
Guo-Ming Shi,
Ai-Wu Ke, Xiao-Ying Wang,
Kang Song,
Zhi Dai,
Ying-Hao Shen,
Jia Fan
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ABSTRACT: Understanding the roles of mammalian autophagy in cancer highlights recent advances in the pharmacologic manipulation of autophagic pathways as a therapeutic strategy for cancer. However, autophagy status and corresponding functions in hepatocellular carcinoma (HCC) after therapeutic stress remain to be clarified. This study was to determine whether the autophagic machinery could be activated after chemotherapy and the contribution of autophagy to tolerance of oxaliplatin in HCC.
Autophagy activation and cell death induced by oxaliplatin were examined in two HCC cell lines as well as in vivo using an HCC model in nude mice. HCC tissue samples with or without locoregional chemotherapy before surgery were also examined by immunohistochemical and electron microscopic analysis.
Autophagy was functionally activated in HCC cell lines and xenografts after oxaliplatin treatment. Suppression of autophagy using either pharmacologic inhibitors or RNA interference of essential autophagy gene enhanced cell death induced by oxaliplatin in HCC cells. Generation of reactive oxygen species has an important role in the induction of cell death by oxaliplatin in combination with autophagy inhibitors. Critically, the combination of oxaliplatin with autophagy inhibitor chloroquine resulted in a more pronounced tumor suppression in HCC xenografts. Furthermore, autophagy-specific protein LC3 and autophagic autophagosome formation were induced to a significantly higher level in HCC specimens that had been subjected to locoregional chemotherapy.
Autophagy activation under therapy stress contributes to HCC tumor cell survival. Targeting the autophagy pathway is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in HCC patients.
Clinical Cancer Research 08/2011; 17(19):6229-38. · 7.74 Impact Factor
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Qiang Gao,
Jian Zhou, Xiao-Ying Wang,
Shuang-Jian Qiu,
Kang Song,
Xiao-Wu Huang,
Jian Sun,
Ying-Hong Shi,
Bai-Zhou Li,
Yong-Sheng Xiao,
Jia Fan
[show abstract]
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ABSTRACT: The density of tumor-infiltrating immunocytes (TICs) has been proposed as an independent predictor of intrahepatic recurrence in patients with hepatocellular carcinoma (HCC). However, the relative roles of TIC density in predicting tumor extrahepatic metastasis remain to be elucidated.
The densities of CD3(+), CD8(+), granzyme B(+), FoxP3(+), CD45RO(+), CD20(+), CD1a(+), CD83(+), CD57(+), and CD68(+) TICs were assessed by immunohistochemistry in tissue microarrays containing paired intratumoral (IT) and peritumoral (PT) tissues from 206 consecutive HCC patients who underwent liver transplantation. Occurrence of extrahepatic metastasis, recurrence-free survival (RFS), and cancer-specific survival (CSS) were assessed retrospectively in relation to TIC densities.
CD45RO(+) memory T cell density was lower in tumor tissue compared with peritumor, whereas CD57(+) senescent T cell density was higher. Univariate analysis revealed that increased CD45RO (IT) (+) and decreased CD57 (PT) (+) densities were statistically significantly associated with favorable RFS and CSS, while other types of TICs, intratumorally or peritumorally, showed no prognostic values. Further, the CD45RO (IT) (+) /CD57 (PT) (+) ratio could stratify patients more accurately in terms of RFS and CSS than either marker used alone. Finally, multivariate analysis indicated that a high CD45RO (IT) (+) /CD57 (PT) (+) ratio was independently associated with better RFS (hazard ratio [HR] = 0.64; 95% confidence interval [CI], 0.42 to 0.98; P = 0.040) and CSS (HR = 0.51; 95% CI, 0.31 to 0.83; P = 0.007), but not CD45RO (IT) (+) or CD57 (PT) (+) individually.
These results suggest that the CD45RO (IT) (+) /CD57 (PT) (+) (memory/senescent T cell) ratio is of vital importance in preventing HCC extrahepatic metastasis and in particular demonstrates its independent prognostic value in liver transplant recipients.
Annals of Surgical Oncology 07/2011; 19(2):455-66. · 4.17 Impact Factor
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ABSTRACT: In a resent study by Wang et al (Hepatology. 2011;53: 1932-1943.), Chang cell line was used as a hepatocellular carcinoma cell line with low invasive potential. However, based on isoenzyme analysis, HeLa marker chromosomes, and DNA fingerprinting, Chang liver cell line was found to have been established via HeLa cell contamination. The misuse of this cell line appears to be relatively more frequent in works originating from emerging countries (South Korea, India,…), and particularly from China. In addition to Chang cell line, recent studies have shown that 18% to 36% of cell lines were incorrectly designated.It is likely that new false cell lines continue to be established without the knowledge of their originators. Meanwhile, detecting false cell lines is increasingly difficult as numbers and varieties of circulating cell lines increase. Resolution of the problem of misidentification and cross-contamination requires the conscientization and collaboration of all involved actors: users (including originators) of cell lines, cell banks, journals and funding agencies. (HEPATOLOGY 2011.).
Hepatology 06/2011; 54(5):1894-5. · 11.66 Impact Factor
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ABSTRACT: The tumor stroma is a source of many potential new tumor biomarkers, in which the immune response is of major importance. Little is known regarding how changes in stromal gene expression affect hepatocellular carcinoma (HCC) progression. We analyzed the expression of 28 stroma-related genes using quantitative RT-PCR in 122 HCC samples, and related the results to patient prognosis. Hierarchical clustering based on expression of the 28 genes, or the 6-Th1 cell markers, can classify HCC patients into prognostically different subgroups. We further identified a five-gene classifier (protective genes IRF1 and GZMB and risk genes CRTH2, VEGF, and MMP7) as a significant independent prognosticator for recurrence (hazard ratio [HR], 4.80; 95% confidence interval [CI], 2.31-9.96; P = 2.6 × 10(-5) ) by multivariate analyses. Importantly, the classifier was further validated in an independent set of 172 HCC samples (HR, 2.21; 95% CI, 1.20-3.00; P = 0.002). The predictive ability of the classifier, as measured by area under the curve (0.713 and 0.613 for original and validation cohorts, respectively), was comparable to those of vascular invasion, Barcelona Clinic Liver Cancer stage, and TNM stage. The densities of various tumor stromal cells were analyzed by immunostaining. Comparing the immunostaining and gene expression data showed significant association of the gene classifier with the amount of reactive stroma in both cohorts. Thus, the signature reveals the strong prognostic capacity of immune responses, angiogenic activity, and ECM remodeling, highlighting the importance of stromal biology in HCC progression. Contained in this novel predictor may be targets suitable for new therapeutic interventions, or for use as independent prognosticators.
Cancer Science 05/2011; 102(8):1522-31. · 3.33 Impact Factor
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ABSTRACT: Overexpression of CD151 is associated with poor prognosis for hepatocellular carcinoma (HCC), yet its role in pathogenesis is not known.
We analyzed the expression of the integrin subunit α6 by quantitative, real-time polymerase chain reaction and immunoblot analyses of 120 HCC tissue samples; its clinical significance was investigated using tissue microarray (TMAs) analysis of samples from 335 patients with HCC. Immunoprecipitation was used to assess the relationship between α6 and CD151. The molecular effects of high expression levels of α6 and CD151 in HCC cells were determined using RNA interference and pharmacologic approaches.
Overexpression of α6 correlated with poor prognosis of patients with HCC; α6 formed a complex with endogenous CD151 in HCC cells. In cells that expressed high levels of α6 and CD151, laminin-5 promoted cell spreading by inducing the epithelial-mesenchymal transition (EMT); this effect was not observed in cells that expressed high levels of only α6 or CD151. Cells that expressed high levels of α6 and CD151 underwent the EMT in response to laminin-5, through hyperactivation of phosphatidylinositol-3-kinase (PI3K), primarily induced via the PI3K-protein kinase B (Akt)-Snail-phosphatase and tensin homolog feedback pathway. The EMT was reversed by PI3K inhibitors and antibodies against CD151 or α6 in vitro, and was delayed by specific interference with CD151 and α6 in vivo.
High expression levels of CD151 and α6 promote invasiveness of HCC cells. Either of these proteins, or PI3K signaling, might be targets for therapeutics for subgroups of patients with HCC.
Gastroenterology 02/2011; 140(5):1629-41.e15. · 11.68 Impact Factor
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Ranjan Prasad Devbhandari,
Guo-Ming Shi,
Ai-Wu Ke,
Fei-Zhen Wu,
Xiao-Yong Huang, Xiao-Ying Wang,
Ying-Hong Shi,
Zhen-Bin Ding,
Yang Xu,
Zhi Dai,
Jia Fan,
Jian Zhou
[show abstract]
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ABSTRACT: Tetraspanin CD151 has been implicated in metastasis through forming complexes with different molecular partners. In this study, we mapped tetraspanin web proteins centered on CD151, in order to explore the role of CD151 complexes in the progression of hepatocellular carcinoma (HCC). Immunoprecipitation was used to isolate tetraspanin complexes from HCCLM3 cells using a CD151 antibody, and associated proteins were identified by mass spectrometry. The interaction of CD151 and its molecular partners, and their roles in invasiveness and metastasis of HCC cells were assayed through disruption of the CD151 network. Finally, the clinical implication of CD151 complexes in HCC patients was also examined. In this study, we identified 58 proteins, characterized the tetraspanin CD151 web, and chose integrin β1 as a main partner to further investigate. When the CD151/integrin β1 complex in HCC cells was disrupted, migration, invasiveness, secretion of matrix metalloproteinase 9, and metastasis were markedly influenced. However, both CD151 and integrin β1 expression were untouched. HCC patients with high expression of CD151/integrin β1 complex had the poorest prognosis of the whole cohort of patients. Together, our data show that CD151 acts as an important player in the progression of HCC in an integrin β1-dependent manner.
PLoS ONE 01/2011; 6(9):e24901. · 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
[show abstract]
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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,
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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ABSTRACT: Liver-intestine cadherin (LI-cadherin; CDH-17) is a new member of the cadherin superfamily with distinct structural and functional features. The study was designed to investigate the role of LI-cadherin in tumor invasion and prognosis of human hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC).
LI-cadherin expression in HBV-positive hepatocellular carcinoma cell lines with low- and high-invasive potentials was evaluated by Western-blot, immunofluorescence, and real-time polymerase chain reaction (PCR) analyses. The role of LI-cadherin in tumor invasion was also evaluated in vitro by a small-interfering ribonucleic acid (siRNA)-mediated approach. The prognostic significance of LI-cadherin was validated in a cohort of HBV-positive HCC patients by immunohistochemistry and Western-blot.
Significant high levels of LI-cadherin mRNA and protein were found in the high-invasive HCCLM3 as compared with those in low-invasive PLC/PRF/5 and Hep3B cell line. Cell migration, adhesion to extracellular matrix, and matrigel invasion were significantly reduced after LI-cadherin knockdown in HCCLM3 cells. Immunohistochemical analysis of 255 HBV-positive HCC cases showed that overexpression of LI-cadherin was well correlated with microvascular invasion, which was confirmed by Western-blot in 32 tumor tissues, and its overexpression was strongly associated with shorter overall survival as well as higher incidence of tumor recurrence.
LI-cadherin is predictive of microvascular invasion and poor prognosis of HBV-positive HCC, and would be a potential useful intervention target for HCC.
Cancer 08/2009; 115(20):4753-65. · 4.77 Impact Factor
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Qiang Gao, Xiao-Ying Wang,
Shuang-Jian Qiu,
Ichiro Yamato,
Masayuki Sho,
Yoshiyuki Nakajima,
Jian Zhou,
Bai-Zhou Li,
Ying-Hong Shi,
Yong-Sheng Xiao,
Yang Xu,
Jia Fan
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ABSTRACT: The aberrant expression of programmed cell death 1 ligands 1 and 2 (PD-Ls) on tumor cells dampens antitumor immunity, resulting in tumor immune evasion. In this study, we investigated the expression of PD-Ls in human hepatocellular carcinoma (HCC) to define their prognostic significance after curative surgery.
Immunohistochemistry was used to investigate PD-Ls expression as well as granzyme B+ cytotoxic and FoxP3+ regulatory T cell infiltration on tissue microarrays containing 240 randomly selected HCC patients who underwent surgery. The results were further verified in an independent cohort of 125 HCC patients. PD-Ls expression on HCC cell lines was detected by Western blot assay.
Patients with higher expression of PD-L1 had a significantly poorer prognosis than patients with lower expression. Although patients with higher expression of PD-L2 also had a poorer survival, the difference in recurrence was not statistically significant. Multivariate analysis identified tumor expression of PD-L1 as an independent predictor for postoperative recurrence. No correlation was found between PD-Ls expression and granzyme B+ lymphocyte infiltration, whereas a significant positive correlation was detected between PD-Ls expression and FoxP3+ lymphocyte infiltration. In addition, tumor-infiltrating cytotoxic and regulatory T cells were also independent prognosticators for both survival and recurrence. The prognostic value of PD-L1 expression was validated in the independent data set.
Our data suggest for the first time that PD-L1 status may be a new predictor of recurrence for HCC patients and provide the rationale for developing a novel therapy of targeting the PD-L1/PD-1 pathway against this fatal malignancy.
Clinical Cancer Research 03/2009; 15(3):971-9. · 7.74 Impact Factor
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Lu Wang,
Jia Fan,
Lun-xiu Qin,
Hui-chuan Sun,
Qing-hai Ye,
Jin-cai Wu,
Dou-sheng Bai, Xiao-ying Wang,
Yi-feng He,
Qi Pan,
Pei Chen,
Jian Zhou,
Zhao-you Tang
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ABSTRACT: To assess the feasibility, safety and outcome of anatomical laparoscopic left lateral hepatic lobectomy for benign and malignant liver tumors.
From April 2005 to May 2008, 11 patients (7 male, 4 female; mean age 51.7 years) underwent anatomical laparoscopic left lateral hepatic lobectomy. Four patients presented with hepatocellular carcinoma and cirrhosis, while 1 patient had metastatic liver tumors from postoperatively colon cancer, five patients had hemangioma (2 cases with gallstones underwent cholecystectomy), 1 patient had a huge symptomatic angiolipoleiomyoma. Mean tumor size was 5.8 cm (range 2.1 to 12.0 cm). All the lesions were localized in the anatomical left lateral lobe (segments II to III).
The mean operative time was 147 min (range 120 to 180 min). There were no intraoperative or postoperative complications, and blood transfusions were not required. The mean postoperative hospital stay was 5.9 days.
Anatomical laparoscopic left lateral hepatic lobectomy are feasible and safety.
Zhonghua wai ke za zhi [Chinese journal of surgery] 12/2008; 46(21):1621-3.
