Jia Fan

Fudan University, Shanghai, Shanghai Shi, China

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Publications (287)1254.12 Total impact

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    ABSTRACT: The expression of 5-hydroxymethylcytosine (5-hmC) and isocitrate dehydrogenase 2 (IDH2) is frequently downregulated in numerous cancers. 5-hmC and IDH2 expression in hepatocellular carcinoma (HCC) has yet to be determined. The immunohistochemical expression of 5-hmC and IDH2 were analyzed in tissue microarrays containing samples from 646 patients who had undergone hepatectomy for histologically proven HCC. The prognostic value of 5-hmC and IDH2 were evaluated by Cox regression and Kaplan-Meier analyses. We discovered that low 5-hmC and IDH2 expression was associated with malignant behaviors. Low 5-hmC or IDH2 expression alone and combined 5-hmC and IDH2 expression were associated with lower overall survival (OS) rates and higher cumulative recurrence rates. Multivariate analysis indicated that 5-hmC or IDH2 and 5-hmC/IDH2 were independent prognostic indicators for OS and time to recurrence (TTR), which was confirmed in an independent validation cohort. 5-hmC and IDH2 correlate with less aggressive tumor behavior in HCC. When 5-hmC and IDH2 are considered together, they serve as a prognostic marker in patients with surgically resected HCCs.
    Journal of Experimental & Clinical Cancer Research 04/2014; 33(1):32. · 3.07 Impact Factor
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    ABSTRACT: Previous research showed that microRNA-612(miR-612) has inhibitory effects on cell proliferation, migration, invasion, and metastasis of hepatocellular carcinoma (HCC). AKT2 was confirmed to be a direct target of miR-612, through which the epithelial-mesenchymal transition (EMT) and metastasis of HCC were inhibited. Our present findings reveal that miR-612 is able to suppress the stemness of HCC by reducing the number and size of tumorspheres as well as clone formation in soft agar, and to relieve drug resistance to cisplatin and 5-fluorouracil. In addition, miR-612 hampered the capacity of tumorigenesis in NOD/SCID mice and redistributed the tumor invasive frontier of miR-612-modulating cells. Finally, our findings suggest that Wnt/β-catenin signaling is required in the regulation of EMT-associated stem cell-like traits by miR-612.
    Biochemical and Biophysical Research Communications 04/2014; · 2.41 Impact Factor
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    ABSTRACT: The MAPK phosphatases (MKPs) are a family of dual-specificity phosphatases (DUSPs) that can dephosphorylate both phosphothreonine and phosphotyrosine residues, thus inactivating MAPK signaling. DUSP6 is a cytoplasmic MKP that can inactivate ERK. DUSP6 has been implicated in the development of some tumors. The aim of this research was to investigate the expression of DUSP6 in hepatocellular carcinoma (HCC) and the correlation of DUSP6 with mitogen-activated protein kinases (MAPKs), clinicopathological characteristics, and prognosis. Tissues from 305 patients who had undergone hepatectomy for HCC was used in this study. The expression of DUSP6, p-ERK, p-JNK, and p-p38α was determined using tissue microarrays for immunohistochemical analysis. The prognostic value of DUSP6 and other clinicopathological factors were evaluated. The expression of DUSP6 was significantly higher in the tumor tissue when compared to the peritumor or normal liver tissue (P < 0.001). Tumor DUSP6 expression was significantly associated with disease-free survival (DFS) (P = 0.013). Tumor DUSP6 expression was an independent prognostic factor for DFS (Hazard ratio = 1.635, P = 0.006). DUSP6 is over expressed in tumor tissue compared to peritumor or normal liver tissue. Higher expression of DUSP6 in tumor tissue, than in peritumor tissue, is associated with the recurrence after curative resection of HCC, and the relative tumor DUSP6 expression has good power to predict the recurrence of HCC.
    Chinese medical journal 04/2014; 127(7):1211-7. · 0.90 Impact Factor
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    ABSTRACT: Acute rejection (AR) and acceptance of allograft after liver transplantation (LTx) remain critical issues that need addressing to improve prognosis. Therefore we performed rat orthotopic LTx and proteomic analyses to screen for immune response-related biomarkers in sera. Markers identified were validated at the mRNA and/or protein levels and the molecules of interest were functionally explored. Compared to syngeneic controls, signs of AR as well as spontaneous acceptance were observed in hematoxylin and eosin (HE)-stained sections of liver allografts. In accordance with the severity of AR, 30 protein spots displaying significant changes in abundance were identified using two-dimensional differential gel electrophoresis. Ultimately, 14 serum proteins were sequenced and 5 spots of interest identified as hemopexin (HPX). Expression of HPX was significantly and inversely associated with the severity of AR at both the mRNA and protein levels. In vitro, Mt-1, Ho-1, Fth, Inf-γ and Il-17 transcripts were significantly upregulated in lysates of lymphocytes stimulated with HPX, while Il-10 markedly was remarkably downregulated. INF-γ, IL-10 and IL-17 proteins in the supernatant of HPX-stimulated lymphocytes were significantly altered in keeping with the mRNA level. Our data facilitated the generation of a proteomic profile to enhance the understanding of rat liver AR. In view of finding that the HPX serum level is negatively associated with severity of AR of rat liver allograft, we propose that in vitro treatment with HPX regulates cytokine expression in rat lymphocytes.
    Shock (Augusta, Ga.) 03/2014; · 2.87 Impact Factor
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    ABSTRACT: Expression of heterogeneous nuclear ribonucleoprotein AB (hnRNPAB) has been reported to be dysregulated in tumors but its specific contributions to tumor formation and progression are not fully understood. Here, we demonstrate that hnRNPAB is overexpressed in highly metastatic cells and tumor tissues from hepatocellular carcinoma (HCC) patients with recurrence. We found that hnRNPAB overexpression promoted epithelial-mesenchymal transition (EMT) in a manner associated with HCC metastasis in vitro and in vivo. RNAi-mediated silencing of the EMT factor Snail attenuated hnRNPAB-enhanced cell invasion in vitro and lung metastasis in vivo. Mechanistically, HnRNPAB acted to transactivate Snail transcription, which in turn inhibited transcription of the pivotal Snail target gene E-cadherin. Overexpression of hnRNPAB in HCC samples correlated with higher Snail levels, shorter overall survival and higher tumor recurrence. HnRNPAB overexpression, alone or in combination with Snail, was found to be a significant independent risk factor for recurrence and survival after curative resection. In conclusion, our findings define hnRNPAB as an activator of EMT and metastasis in HCC that predicts poor clinical outcomes.
    Cancer Research 03/2014; · 8.65 Impact Factor
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    ABSTRACT: Studies have highlighted important features of the nucleocytoplasmic transport of mRNAs and proteins. Nuclear RNA export factor 3 (NXF3) is a member of the nuclear RNA export factor family that plays a role in mediating the export of cellular mRNA from the nucleus to the cytoplasm for translation. However, little is known about the clinical significance of NXF3 in human tumors. To evaluate the prognostic significance of NXF3 in hepatocellular carcinoma (HCC), the expression levels of NXF3 in a cohort of 112 patients with primary HCC who had undergone hepatectomy for histologically confirmed HCC were assessed by immunohistochemistry. It was identified that the expression levels of NXF3 were higher in the primary HCC tissues compared with those in paired peritumoral liver tissues. The overexpression of NXF3 in the HCC tissues was correlated with decreased survival time [hazard ratio (HR) = 1.954, 95% confidence interval (CI) = 1.034-3.695, P=0.039] and earlier tumor recurrence (HR = 2.101, 95% CI = 1.186-3.722, P=0.011) in postoperative patients with HCC. Notably, overexpression of NXF3 was correlated with a poor survival time and increased recurrence following HCC resection in male patients (P=0.020 and P=0.007, respectively) but not in female patients (P=0.916 and P=0.821, respectively). In conclusion, the findings provide evidence that implicates NXF3 as a prospective predictor of HCC prognosis as well as a potential therapeutic target for cancer treatment.
    Oncology letters 03/2014; 7(3):641-646. · 0.24 Impact Factor
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    ABSTRACT: Recent studies show the incidence of chronic obstructive pulmonary disease (COPD) has remained high in southwest China despite the 1976 National Stove Improvement Program for indoor air quality. Chinese waterpipe smoking, which has been rendered less harmful under the assumption that no charcoal is used and water filters tobacco smoke, is popular in China. We investigated whether Chinese waterpipe use and exposure are associated with risk of COPD. This multicenter cross-sectional study enrolled 1238 individuals from 10 towns in the Fuyuan area, Yunnan Province, China. A matched design was used to estimate the impact of active and passive exposure to Chinese waterpipe smoking on COPD risk; multivariate analyses adjusted for other risk factors. We also collected the water of Chinese waterpipes to assess the mutagenicity of major components and simulated the Chinese waterpipe smoke exposure fine particulates (PM2.5) by the High Volume Air Sampler, and individuals' sera to search for the potential protein biomarkers of COPD. Compared to never-smoking controls, the increased risk of COPD was profound for Chinese waterpipe smokers (adjusted OR, 10.61; 95% CI, 6.89-16.34), Chinese waterpipe passive smokers (adjusted OR, 5.50; 95% CI, 3.61-8.38), cigarette smokers (adjusted OR, 3.18; 95% CI, 2.06-4.91), and cigarette passive smokers (adjusted OR, 2.52; 95% CI, 1.62-3.91). Chinese waterpipe use aggravates lungs with more PM2.5 compared to the cigarette. ChemR23 and tissue inhibitor of metalloproteinase-1 may be potential protein biomarkers of COPD. Chinese waterpipe smoking significantly increases the risk for COPD, which includes women who are exposed to the waterpipe smoke. Chinese Clinical Study.org, No: ChiCTR-CCH-12002235; URL: http://www.chictr.org/cn/
    Chest 02/2014; · 5.85 Impact Factor
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    ABSTRACT: Circulating microRNAs are promising biomarkers for non-invasive testing and dynamic monitoring in cancer patients. However, no consensus exists regarding the normalization of circulating microRNAs in the quantification, making the results incomparable. We investigated global circulating microRNA profiles to identify a stable endogenous control for quantifying circulating microRNAs using 3 cohorts (n=544), including 168 control individuals (healthy subjects and those with chronic hepatitis B and cirrhosis) and 376 cancer patients (hepatocellular, colorectal, lung, esophageal, gastric, renal, prostate, and breast cancer patients). GeNorm, NormFinder, and coefficient of variability (CV) were used to select the most stable endogenous control, whereas Ingenuity Pathway Analysis (IPA) was adopted to explore its signaling pathways. Seven candidates (miR-1225-3p, miR-1228, miR-30d, miR-939, miR-940, miR-188-5p, and miR-134) from microarray analysis and 4 commonly used controls (miR-16, miR-223, let-7a, and RNU6B) from literature were subjected to real-time quantitative reverse transcription-polymerase chain reaction validation using independent cohorts. MiR-1228 (CV=5.4%) with minimum M value and S value presented as the most stable endogenous control across 8 cancer types and 3 controls. IPA showed miR-1228 to be involved extensively in metabolism-related signal pathways and organ morphology, implying that miR-1228 functions as a housekeeping gene. Functional network analysis found that "hematological system development" was on the list of the top networks that associate with miR-1228, implying that miR-1228 plays an important role in the hematological system. The results explained the steady expression of miR-1228 in the blood. In conclusion, miR-1228 is a promising stable endogenous control for quantifying circulating microRNAs in cancer patients. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 02/2014; · 6.20 Impact Factor
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    ABSTRACT: Virus-induced hepatocarcinogenesis involves a series of histological developmental processes with the step-wise acquisition of several genetic changes that are necessary for the malignant transformation of hepatocytes. Although genetic alterations are known to be involved in the pathogenesis of hepatocellular carcinoma (HCC), little is known about the contributions of specific genes to this process. To gain insight into the genetic alterations involved in the neoplastic evolution from chronic hepatitis B virus infection to dysplastic nodules (DN) to HCC, we captured and sequenced the exomes of four DNA samples: one DN sample, two HCC samples and one control peripheral blood sample from a single HCC patient. Mutations in the UBE3C gene (encoding ubiquitin ligase E3C) were observed in both tumor tissues. Then, we resequenced the UBE3C gene in a cohort of 105 HCC patients and identified mutations in 17 out of total 106 (16.0%) HCC patients. The subsequent experiments showed that UBE3C promoted HCC progression by regulating HCC cells epithelial-mesenchymal transition. Clinically, a tissue microarray study of a cohort containing 323 HCC patients revealed that the overexpression of UBE3C in primary HCC tissues correlated with decreased survival (hazard ratio [HR] = 1.657, 95% confidence interval [CI] = 1.220-2.251, P = 0.001) and early tumor recurrence (HR = 1.653, 95% CI = 1.227-2.228, P = 0.001) in postoperative HCC patients. Conclusion: Our findings indicate that UBE3C is a candidate oncogene involved in tumor development and progression and therefore a potential therapeutic target in applicable HCC patients. (Hepatology 2014;).
    Hepatology 01/2014; · 12.00 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most serious health problems worldwide. As in many other diseases, environment and genetic factors are believed to be involved in the pathogenesis of HCC. Numerous epidemiologic investigations including case-control and cohort studies have suggested the association of glutathione S-transferase (GST) genetic polymorphisms and HCC risk. However, some studies have produced conflicting results. Therefore, we performed an updated meta-analysis to clarify this inconsistency and to establish a comprehensive picture of the association of the polymorphisms of GSTM1 and GSTT1 with HCC susceptibility. We searched PubMed, Embase, ISI Web of Science, and CNKI databases to identify eligible studies meeting the inclusion criteria up to August 30, 2013. Odds ratios (ORs) and 95 % confidence intervals (CIs) were used to assess the strength of association. Finally, there were a total of 33 studies with 4,232 cases and 6,601 controls included in this meta-analysis. In the pooled analysis, significantly increased HCC risks were found for null genotype of GSTM1 (OR = 1.31, 95 % CI = 1.07-1.61, P = 0.010, P heterogeneity < 10(-5)) and GSTT1 (OR = 1.47, 95 % CI = 1.25-1.74, P < 10(-5), P heterogeneity < 10(-5)). Potential sources of heterogeneity were explored by subgroup analysis based on ethnicity, sample size, and source of control. Significant results were found among East Asians and Indians when stratified by ethnicity, while no evidence of significant associations was observed among Caucasian and African populations. In the gene-gene interaction analysis, a statistically significant increased risk for HCC was detected for individuals with combined deletion mutations in both genes compared to those with wild genotypes (OR = 1.88, 95 % CI = 1.41-2.50, P < 10(-4), P heterogeneity = 0.004). The present meta-analysis demonstrated that the GSTM1 and GSTT1 null genotype may be associated with an increased risk of HCC and that individuals having the combination of both defective GST genotypes may be more susceptible to developing HCC.
    Tumor Biology 01/2014; · 2.52 Impact Factor
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    ABSTRACT: GATA family of transcription factors are critical for organ development and associated with progression of various cancer types. However, their expression patterns and prognostic values for hepatocellular carcinoma (HCC) are still largely unknown. Expression of GATA transcription factors in HCC cell lines and tissues (n = 240) were evaluated by RT-qPCR, western blot and immunohistochemistry. Cellular proliferation, migration and invasion of HepG2 was evaluated by CCK-8 kit, scratch wound assay and transwell matrigel invasion assay, respectively. GATA2 expression was decreased in HCC cell lines (p = 0.056 for mRNA, p = 0.040 for protein) and tissues (p = 1.27E-25) compared with normal hepatocytes. Decreased expression of intratumoral GATA2 protein significantly correlated with elevated alpha feto-protein (p = 2.7E-05), tumor size >5 cm (p = 0.049), absence of tumor capsule (p = 0.002), poor differentiation (p = 0.005), presence of tumor thrombi (p = 0.005) and advanced TNM stage (p = 0.001) and was associated with increased recurrence rate and decreased overall survival rate by univariate (p = 1.6E-04 for TTR, p = 1.7E-04 for OS) and multivariate analyses (HR = 0.63, 95% CI = 0.43-0.90, p = 0.012 for TTR; HR = 0.67, 95% CI = 0.47-0.95, p = 0.026 for OS). RNAi-mediated knockdown of GATA2 expression significantly enhanced proliferation, migration and invasion of HepG2 cell in vitro. Decreased expression of hematopoietic factor GATA2 was associated with poor prognosis of HCC following resection.
    PLoS ONE 01/2014; 9(1):e87505. · 3.73 Impact Factor
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    ABSTRACT: Background & Aims Pathogenesis of intrahepatic cholangiocarcinoma (ICC), the second-most common hepatic cancer, is a poorly understood and its incidence is increasing worldwide. We searched for mutations in human ICC tumor samples and investigated how they affect ICC cell function. Methods We performed whole-exome sequencing of 7 paired ICCs and their surrounding, non-tumor tissues to detect somatic alterations. We then screened 124 pairs of ICC and non-tumor samples for these mutations, including 7 exomes. We compared mutations in PTPN3 with tumor recurrence in 124 patients, and PTPN3 expression levels with recurrence in 322 patients (the combination of both in 86 patients). The functional effects of PTPN3 variations were determined by RNA interference and transgenic expression in cholangiocarcinoma cell lines (RBE, HCCC-9810, and Huh28). Results Based on exome sequencing, pathways that regulate protein phosphorylation were among the most frequently altered in ICC samples, and genes encoding protein tyrosine phosphatases (PTPs) were among the most frequently mutated. We identified mutations in 9 genes encoding PTPs in 4/7 ICC exomes. In the prevalence screen of 124 paired samples, 51.6% of ICCs contained somatic mutations in at least 1/9 PTP genes; 41.1% had mutations in PTPN3.Transgenic expression of PTPN3 in cell lines increased cell proliferation, colony formation, and migration. PTPN3L232R and PTPN3L384H, which were frequently detected in ICC samples, were found to be gain-of-function mutations; their expression in cell lines further increased cell proliferation, colony formation, and migration. ICC-associated variants of PTPN3 had altered phosphatase activity. Patients whose tumors contained activating mutations or higher levels of PTPN3 protein than non-tumor tissues had higher rates of disease recurrence than patients without. Conclusions Using whole-exome sequencing of ICC samples from patients, we found that more than 40% contain somatic mutations in PTPN3. Activating mutations in and high expression levels of PTPN3 were associated with tumor recurrence in patients.
    Gastroenterology 01/2014; · 12.82 Impact Factor
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    ABSTRACT: Objectives: TCR- gamma-delta + T cells (γδ T cells) are non-conventional T lymphocytes that can recognize and eradicate tumor cells. Our previous studies showed that infiltration and function of γδT cells were substantially attenuated in hepatocellular carcinoma (HCC). However, their prognostic value was not clarified. Methods: The association between γδ T cells and the clinical outcomes was determined by immunohistochemistry (IHC) in a HCC patient cohort (n = 342). Results:Immunohistochemistry showed decreased infiltration of γδ T cells in tumoral tissues compared with paired peritumoral tissues. The counts of γδ T cells in peritumoral tissues were negatively correlated with tumor size (P = 0.005). Survival analysis showed that the levels of peritumoral γδ T cells were related to both time to recurrence (TTR) and overall survival (OS) (P = 0.010 and P = 0.036, respectively) in univariate analysis, and related to TTR in multivariate analysis (P = 0.014, H.R. [95% CI] = 0.682 [0.502-0.927]). Furthermore, the level of peritumoral γδ T cells showed independent prognostic value for TTR in Barcelona Clinic Liver Cancer (BCLC) stage A patients (P = 0.038, H.R. [95% CI] = 0.727 [0.537-0.984]). However, tumoral γδ T cells did not show independent prognostic value for either TTR or OS in HCC patients. Conclusions: Low counts of γδ T cells in peritumoral liver tissue are related to a higher incidence of recurrence in HCC and can predict postoperative recurrence, especially in those with early-stage HCC.
    Asian Pacific journal of cancer prevention: APJCP 01/2014; 15(2):775-80. · 1.27 Impact Factor
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    ABSTRACT: Previous research showed that microRNA-612(miR-612) has inhibitory effects on cell proliferation, migration, invasion, and metastasis of hepatocellular carcinoma (HCC). AKT2 was confirmed to be a direct target of miR-612, through which the epithelial–mesenchymal transition (EMT) and metastasis of HCC were inhibited. Our present findings reveal that miR-612 is able to suppress the stemness of HCC by reducing the number and size of tumorspheres as well as clone formation in soft agar, and to relieve drug resistance to cisplatin and 5-fluorouracil. In addition, miR-612 hampered the capacity of tumorigenesis in NOD/SCID mice and redistributed the tumor invasive frontier of miR-612-modulating cells. Finally, our findings suggest that Wnt/β-catenin signaling is required in the regulation of EMT-associated stem cell–like traits by miR-612.
    Biochemical and Biophysical Research Communications 01/2014; · 2.41 Impact Factor
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    ABSTRACT: In hepatocellular carcinoma (HCC), biomarkers for prediction of prognosis and response to immunotherapy such as interferon-α (IFN-α) would be very useful in the clinic. We found that expression of retinoic acid-inducible gene-I (RIG-I), an IFN-stimulated gene, was significantly downregulated in human HCC tissues. Patients with low RIG-I expression had shorter survival and poorer response to IFN-α therapy, suggesting that RIG-I is a useful prognosis and IFN-α response predictor for HCC patients. Mechanistically, RIG-I enhances IFN-α response by amplifying IFN-α effector signaling via strengthening STAT1 activation. Furthermore, we found that RIG-I deficiency promotes HCC carcinogenesis and that hepatic RIG-I expression is lower in men than in women. RIG-I may therefore be a tumor suppressor in HCC and contribute to HCC gender disparity.
    Cancer cell 12/2013; · 25.29 Impact Factor
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    ABSTRACT: CXCL5 is a member of the CXC-type chemokine family that may play a role in carcinogenesis and cancer progression. This study investigates the biological function and clinical significance of CXCL5 in intrahepatic cholangiocarcinoma (ICC). We demonstrated that CXCL5 was overexpressed in ICC cell lines and tumour samples compared with paired normal tissues. CXCL5 had a direct chemoattractant effect on neutrophils in vitro through PI3K-Akt and ERK1/2 signalling pathways. In animal studies, CXCL5 promoted tumour growth and metastasis without altering in vitro proliferative and invasive ability of ICC cells, and this effect was mediated by the recruitment of intratumoural infiltrative neutrophils by tumour-derived CXCL5. Immunohistochemical analysis of ICC samples showed that overexpression of CXCL5 correlated strongly with intratumoural neutrophil infiltration, shorter overall survival, and high tumour recurrence. Multivariate analysis revealed that CXCL5 overexpression alone, or combined with the presence of intratumoural neutrophils, was an independent prognostic indicator for ICC. In conclusion, our data showed that CXCL5 promotes ICC growth and metastasis by recruiting intratumoural neutrophils. CXCL5 alone or combined with intratumoural neutrophils is a novel prognostic predictor for ICC patients and a potential therapeutic target.
    Carcinogenesis 11/2013; · 5.64 Impact Factor
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    ABSTRACT: Genetic epidemiological data in hepatocellular carcinoma (HCC) pedigrees indicate a pattern of X-linked recessive inheritance of HCC susceptibility genes. This study is designed to test the hypothesis that there are genes conferring susceptibility to HCC located on the X-chromosome. An X-chromosomal association study was conducted among Chinese men recruited from an area with a high prevalence of HCC. The candidate gene was further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). By analyzing 5454 X-chromosome single nucleotide polymorphisms (SNPs) in 50 HCC patients and 50 controls, we found two promising regions in which the associated SNPs clustered, located at Xq22.1 and Xq26.2. We further selected 35 tag SNPs (tSNPs) from these two regions for additional genotyping analysis in another independent set of 290 cases and 242 controls. Notably, SNP rs5945919 at Xq22.1 exhibited a significant association with HBV-related HCC (odds ratio [OR]=2.22, 95% confidence interval [CI]=1.15-4.30, P=0.016). The expressions of the three genes near the rs5945919 locus, RAB40AL, BEX1, and NXF3, were analyzed by qRT-PCR between another 24 HCC tissues and paired peritumoral liver tissues. The results indicated that NXF3, rather than RAB40AL and BEX1, mRNA level was found to be more abundant in HCC tissue than in peritumoral liver tissue. Our findings implicated Xq22.1 as a novel susceptibility locus for HCC and NXF3 as a candidate risk factor for relevant HCC.
    Gastroentérologie Clinique et Biologique 10/2013; · 0.80 Impact Factor
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    ABSTRACT: Prognostic factors and adjuvant therapy of intrahepatic cholangiocarcinoma (ICC) after curative resection were not clear. We aim to analyze prognostic factors after curative resection and evaluate adjuvant therapy and survival based on the new staging system. A retrospective analysis of 283 patients who underwent surgical exploration for ICC was performed. Staging was performed according to the 7(th) edition AJCC staging manual. Univariate and multivariate analyses were used to evaluate independent prognostic factors. The difference for OS at different TNM stages after R0 resection was significant (p<0.001). Despite regional lymph node metastasis, tumor number and vascular invasion, serum GGT level was also an independent prognostic factor for OS of patients after R0 resection. The incidence of biliary and vascular invasion was significantly higher in high GGT group than in normal GGT group. Factors predictive of recurrence were multiple tumors and regional lymph node metastasis. After R0 resection, adjuvant TACE not only did not improve the OS of patients at TNM stage I (p=0.508), but significantly promoted recurrence of these patients (p=0.006). Only patients at TNM stage II, III and IV benefited from adjuvant TACE for longer survival, while the recurrence rates were not affected. The new staging system can predict the survival of ICC patients after R0 resection. High GGT level may be suggestive of biliary and vascular invasion and was an independent risk factor for OS after R0 resection. Adjuvant TACE may be indicated only for patients at advanced stages for better survival. This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 10/2013; · 3.87 Impact Factor
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    ABSTRACT: Metastasis is one of the main causes of poor prognosis for hepatocellular carcinoma (HCC), which has been linked to cell-death resistance. Autophagy is an important survival mechanism under conditions of cell stress. We hypothesized that autophagy may play a role in HCC metastasis due to its prosurvival effect. Highly metastatic HCC cell lines with stable autophagy inhibition were established via lentivirus-mediated silencing of BECN1 and ATG5 genes. Mouse models of pulmonary metastasis were then developed using the cells with or without autophagy inhibition. The analysis of lung metastasis by histopathological examination and small animal imaging showed that autophagy inhibition significantly decreased the incidence of pulmonary metastases in vivo. Further invasion, migration, detachment, lung colonization, and epithelial-mesenchymal transition (EMT) assays indicated that autophagy inhibition did not affect cell invasiveness, migration or EMT but attenuated the anoikis-resistance and lung colonization of HCC cells. Investigation of the molecular mechanisms underlying showed that the autophagy-inhibition-mediated anoikis-resistance attenuation was associated with the regulation of apoptotic signaling. As autophagy inhibition was shown to be able to suppress HCC metastasis, an autophagy-based HCC tissue-specific target therapy system (AFP-Cre/LoxP-shRNA) was constructed. In vitro and in vivo analyses showed that the system was able to efficiently inhibit autophagy of HCC cells and tissue in a tissue-specific manner. Further in vivo metastasis assay showed that intratumoral administration of the system could significantly suppress lung metastasis. Together, our findings suggest that autophagy may be involved in HCC metastasis through facilitating anoikis resistance and lung colonization of HCC cells. Autophagy-based HCC tissue-specific target therapy may be a new strategy for the management of HCC metastasis.
    Autophagy 10/2013; 9(12). · 12.04 Impact Factor

Publication Stats

3k Citations
1,254.12 Total Impact Points

Institutions

  • 2001–2014
    • Fudan University
      • Institutes of Biomedical Sciences
      Shanghai, Shanghai Shi, China
  • 2013
    • National Cancer Institute (USA)
      • Laboratory of Human Carcinogenesis
      Maryland, United States
  • 2008–2013
    • Shandong University
      Chi-nan-shih, Shandong Sheng, China
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
  • 2011
    • Shanghai Punan Hospital
      Shanghai, Shanghai Shi, China
  • 2004–2011
    • Shanghai Cancer Institute
      Shanghai, Shanghai Shi, China
  • 2009
    • National Institutes of Health
      • Center for Cancer Research
      Bethesda, MD, United States
    • Hangzhou First People's Hospital
      Hang-hsien, Zhejiang Sheng, China
  • 2007–2009
    • University of Pittsburgh
      • Department of Pathology
      Pittsburgh, PA, United States
    • Moffitt Cancer Center
      Tampa, Florida, United States
  • 1998–2002
    • Shanghai Medical University
      • • Department of Radiology
      • • Liver Cancer Institute
      Shanghai, Shanghai Shi, China