Jia Fan

Fudan University, Shanghai, Shanghai Shi, China

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Publications (352)1621.9 Total impact

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    ABSTRACT: Phosphomannopentaose sulfate (PI-88), an effective inhibitor of heparanase (HPSE), exhibited anti-recurrence and anti-metastasis activity in preliminary clinical trials of hepatocellular carcinoma (HCC); however, the underlying mechanisms remain uncertain. Our aim was to reveal the mechanism by which PI-88 inhibits recurrence and intrahepatic metastasis. A tissue microarray containing samples from 352 HCC patients was used to determine HPSE expression. We performed enzyme-linked immunosorbent assay (ELISA) to detect plasma levels of HPSE in 40 HCC patients. We also used quantitative polymerase chain reaction, western blot analysis, and immunohistochemical staining to assess HPSE expression of HCC cell lines and tissues. The in vitro effects of PI-88 were examined by cell proliferation and migration assays. In vivo PI-88 activity was assessed using murine orthotopic HCC models. Intratumoral HPSE was an independent prognostic marker for postsurgical overall survival (P = 0.001) and time to recurrence (P < 0.001) of HCC patients with hepatectomy. Elevated levels of HPSE were detected both in postsurgical plasma of HCC patients and an orthotopic mouse model after hepatectomy. PI-88 inhibited tumor recurrence and metastasis after liver resection in the mouse model. In vitro expression of HPSE was up-regulated by overexpression of early growth response 1 (EGR1), which is induced after hepatectomy. Up-regulation of HPSE enhanced the sensitivity of HCC cells to PI-88 and the inhibitive effect of PI-88 on cell proliferation and migration. Our data show that PI-88 effectively inhibits postoperative recurrence and intrahepatic metastasis of HCC, providing an experimental basis for the clinical application of PI-88 in HCC patients who have undergone hepatectomy.
    Tumor Biology 09/2015; DOI:10.1007/s13277-015-4085-8 · 3.61 Impact Factor
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    ABSTRACT: There is increasing and consistent evidence concerning the association of systemic inflammation and poor outcome in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify a superior inflammation-based prognostic scoring system for patients with HCC undergoing hepatectomy.We analyzed two independent cohorts of a total of 723 patients with HCC who underwent radical surgery between 2010 and 2012. The prognostic value of the inflammation scores, including the Glasgow Prognostic Score (GPS), modified GPS (mGPS), neutrophil-to-lymphocyte ratio, platelet lymphocyte ratio, prognostic index, and prognostic nutritional index, as well as the Barcelona Clinic Liver Cancer and Cancer of the Liver Italian Program staging systems was analyzed in a test cohort of 367 patients and validated in a validation cohort of 356 patients.A high score with the mGPS was associated with large tumor size, vascular invasion, and advanced clinical stage. Multivariate analysis showed that the mGPS was independently associated with overall survival and disease-free survival, and had a higher area under the curve value in comparison with other inflammation-based scores.The results of this study demonstrated that the mGPS is an independent marker of poor prognosis in patients with resectable HCC and is superior to other inflammation-based scores.
    Medicine 09/2015; 94(36):e1486. DOI:10.1097/MD.0000000000001486 · 5.72 Impact Factor
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    ABSTRACT: Molecular pathogenesis of intrahepatic cholangiocarcinoma (iCCA) is poorly understood and its incidence continues to increase worldwide. Deficiency of MAPK kinase kinase 4 (MAP3K4) has been reported to induce epithelial-mesenchymal transition (EMT) process of placental and embryonic development, yet its role in human cancer remains unknown. Previously, we have found that MAP3K4 had somatic mutation in iCCA. Here, we sequenced all exons of MAP3K4 in 124 iCCA patients and identified 9 somatic mutations in 10 (8.06%) patients, especially in those with lymph node metastasis and intrahepatic metastasis. We also showed that mRNA and protein levels of MAP3K4 were significantly reduced in iCCA than paired nontumor tissues. Furthermore, knockdown of MAP3K4 in cholangiocarcinoma cells markedly enhanced cell proliferation and invasiveness in vitro and tumor progression in vivo, accompanied by a typical EMT process. In contrast, over-expression of MAP3K4 in cholangiocarcinoma cells obviously reversed EMT and inhibited cell invasion. Mechanistically, MAP3K4 functioned as a negative regulator of EMT in iCCA by antagonizing the activity of p38/NF-κB/snail pathway. We found that tumor-inhibitory effect of MAP3K4 was abolished by inactivating mutations. Clinically, a tissue microarray study containing 322 iCCA samples from patients revealed that low MAP3K4 expression in iCCA positively correlated with aggressive tumor characteristics, such as vascular invasion and intrahepatic or lymph node metastases, and was independently associated with poor survival and increased recurrence after curative surgery. MAP3K4, significantly down-regulated, frequently mutated and potently regulating EMT process in iCCA, was a putative tumor suppressor of iCCA. This article is protected by copyright. All rights reserved. © 2015 by the American Association for the Study of Liver Diseases.
    Hepatology 09/2015; DOI:10.1002/hep.28149 · 11.06 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):4814-4814. DOI:10.1158/1538-7445.AM2015-4814 · 9.33 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):5266-5266. DOI:10.1158/1538-7445.AM2015-5266 · 9.33 Impact Factor
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    ABSTRACT: Caveolin-1 is a member of the caveolae family of membrane proteins. Although some researchers have investigated the function of Caveolin-1 in hepatocellular carcinoma, the mechanism of Caveolin-1 action and its prognostic value in hepatocellular carcinoma remain unclear. Caveolin-1 expression was measured in hepatocellular carcinoma cell lines and tissues using quantitative reverse transcription-polymerase chain reaction, western blot, and immunofluorescence assays. In in vitro experiments, Caveolin-1 was depleted using a short hairpin RNA lentiviral vector, and tumor cell behavior was analyzed. The effect of Caveolin-1 on hepatocellular carcinoma cell autophagy was investigated. Prognostic value of Caveolin-1 was analyzed by immunohistochemistry in two cohorts that included a total of 721 hepatocellular carcinoma patients. We found that Caveolin-1 was overexpressed in highly metastatic hepatocellular carcinoma cell lines and tumor tissues. Moreover, Caveolin-1 promoted hepatocellular carcinoma cell proliferation, migration, and angiogenesis and inhibited autophagy. Finally, Caveolin-1 expression in hepatocellular carcinoma tissues was inversely correlated with patient overall survival and time to recurrence. Our data obtained from cell lines suggest an oncogenic role for Caveolin-1 in hepatocellular carcinoma, Caveolin-1 contributed to hepatocellular carcinoma cell autophagy deficiency. Furthermore, Caveolin-1 may function as a novel prognostic indicator for hepatocellular carcinoma patients after curative resection, and combination of targeted therapy aimed at Caveolin-1 and autophagy modulation may represent an effective way to treat hepatocellular carcinoma. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    Gastroentérologie Clinique et Biologique 07/2015; DOI:10.1016/j.clinre.2015.06.017 · 1.64 Impact Factor
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    ABSTRACT: microRNAs (miRNAs) are involved in the various processes of DNA damage repair and play crucial roles in regulating response of tumors to radiation therapy. Here, we used nasopharyngeal carcinoma (NPC) radio-resistant cell lines as models and found that the expression of miR-504 was significantly up-regulated. In contrast, the expression of nuclear respiratory factor 1 (NRF1) and other mitochondrial metabolism factors, including mitochondrial transcription factor A (TFAM) and oxidative phosphorylation (OXPHOS) complex III were down-regulated in these cell lines. At the same time, the Seahorse cell mitochondrial stress test results indicated that the mitochondrial respiratory capacity was impaired in NPC radio-resistant cell lines and in a miR-504 over-expressing cell line. We also conducted dual luciferase reporter assays and verified that miR-504 could directly target NRF1. Additionally, miR-504 could down-regulate the expression of TFAM and OXPHOS complexes I, III, and IV and impaired the mitochondrial respiratory function of NPC cells. Furthermore, serum from NPC patients showed that miR-504 was up-regulated during different weeks of radiotherapy and correlated with tumor, lymph nodes and metastasis (TNM) stages and total tumor volume. The radio-therapeutic effect at three months after radiotherapy was evaluated. Results indicated that patients with high expression of miR-504 exhibited a relatively lower therapeutic effect ratio of complete response (CR), but a higher ratio of partial response (PR), compared to patients with low expression of miR-504. Taken together, these results demonstrated that miR-504 affected the radio-resistance of NPC by down-regulating the expression of NRF1 and disturbing mitochondrial respiratory function. Thus, miR-504 might become a promising biomarker of NPC radio-resistance and targeting miR-504 might improve tumor radiation response.
    Oncotarget 06/2015; 6(18):15995-6018. DOI:10.18632/oncotarget.4138 · 6.36 Impact Factor
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    ABSTRACT: Patients with cirrhosis are at higher risk of developing hepatocellular carcinoma (HCC), the second most frequent cause of cancer-related death. Although HCC diagnosis based on conventional morphological characteristics serves as the “gold standard” in the clinic, there is a high demand for more convenient and effective diagnostic methods that employ new biophysical perspectives. Here, we show that the nanomechanical signature of liver tissue is directly correlated with the development of HCC. Using indentation-type atomic force microscopy (IT-AFM), we demonstrate that the lowest stiffness peak (LSP) in the Young’s modulus distribution of surgically removed liver cancer tissues can serve as a mechanical fingerprint to evaluate the malignancy of liver cancer. Cirrhotic tissues shared the same LSP as normal tissues. However, a noticeable downward shift in the LSP was detected when the cirrhotic tissues progressed to a malignant state, making the tumor tissues more prone to microvascular invasion. Cell-level mechanistic studies revealed that the expression level of a Rho-family effector (mDia1) was consistent with the mechanical trend exhibited by the tissue. Our findings indicate that the mechanical profiles of liver cancer tissues directly varied with tumor progression, providing an additional platform for future diagnosis of HCC.
    Nanoscale 06/2015; 7(30). DOI:10.1039/C5NR02192H · 7.39 Impact Factor
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    Dataset: 23150119f
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    ABSTRACT: Clinical response of hepatocellular carcinoma (HCC) to arsenic trioxide (ATO) has been poor. Promyelocytic leukemia protein (PML) is central to ATO treatment efficacy of acute promyelocytic leukemia. We examine impacts of PML expression on the effectiveness of ATO treatment in HCC. We show that increased PML expression predicts longer survival and lower cancer recurrence rates after HCC resection. However, high PML expression dampens the anti-tumor effects of ATO in HCC cells. Gene microarray analysis shows that reduced PML expression significantly down-regulates expression of aldehyde dehydrogenase 3 family member A1 (ALDH3A1). ALDH3A1 depression facilitates accumulation of ATO-induced reactive oxygen species. Chromatin immunoprecipitation analysis and promoter activity assays confirm that PML regulates ALDH3A1 expression through binding to the promoter region of ALDH3A1. Clinically, ATO treatment decreases the disease progression rate in advanced HCC patients with negative PML expression. In conclusion, PML confers a favorable prognosis in HCC patients, but it induces ATO resistance through ALDH3A1 up-regulation in HCC cells. ATO is effective for HCC patients with negative PML expression. Combining with an ALDH3A1 inhibitor, ATO may be efficacious in patients with positive PML expression. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer letters 06/2015; 366(1). DOI:10.1016/j.canlet.2015.06.014 · 5.62 Impact Factor
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    ABSTRACT: While accumulating evidence has shown that the use of the diabetic drug metformin may be beneficial against various tumors in some epidemiological studies, a few studies failed to show the same beneficial effects. The molecular and cellular mechanisms for these conflicting observations are not clear. In this study, we compared the inhibitory effects of cell growth by metformin on several hepatic tumor cell lines: SMMC-7721, HCC-97L, HCC-LM3 and HepG2. While metformin inhibited cell growth in all these cells, we found that SMMC-7721, HCC-97L and HCC-LM3 cells were more resistant than HepG2 cells. Mechanistically, we found that metformin inhibited mTOR in all these hepatic tumor cells. However, SMMC-7721 cells had higher levels of basal autophagy and mTORC2-mediated feedback activation of Akt than HepG2 cells, which may render SMMC-7721 cells to be more resistant to metformin-induced inhibition of cell growth. Similarly, HCC-97L and HCC-LM3 cells also had higher feedback activation of AKT than HepG2 cells, which may also account for their resistance to metformin-induced inhibition of cell growth. Therefore, the various basal autophagy and mTOR activity in different cancer cells may contribute to the controversial findings on the use of metformin in inhibition of cancers in humans.
    PLoS ONE 06/2015; 10(6):e0130953. DOI:10.1371/journal.pone.0130953 · 3.23 Impact Factor
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    ABSTRACT: Previous studies predicted the prognosis of hepatocellular carcinoma (HCC) mainly based on tumor-related factors, while the impacts of hepatitis B virus (HBV)-related factors are usually ignored. The objective of this exploratory study is to investigate the prognostic role of hepatitis B core antibody (HBcAb) on postoperative survival and recurrence of HCC. A retrospective analysis of 3388 HBsAg positive (HBV-related) HCC patients treated by curative resection were performed. Multivariate analysis of independent prognostic factors was performed by Cox proportional hazards regression model. HBcAb positivity was an independent prognostic factor for recurrence free survival (RFS) of HBV-related patients (p<0.001, HR: 1.723, 95% CI: 1.278-2.324), and the 1-, 3-, 5-year RFS rates for HBcAb negative patients were significantly better than those of HBcAb positive patients (92.5%, 72.1% and 65.9% vs 77.9%, 58.6% and 46.9%, p<0.001). HBcAb positive HCC was much bigger (p=0.006), more often involved with vascular invasion (p=0.001), elevated AFP (p=0.001) and ALT (p=0.046) levels, but less often involved with capsule formation (p=0.034). Besides vascular invasion, tumor size, interferon-α treatment, AFP and GGT level, HBcAb positivity was an independent prognostic factor for early intrahepatic recurrence of HBV-related patients (p=0.025, HR: 1.766, 95% CI: 1.073-2.907), and the majority of HBcAb positive recurrence were early recurrence while most of HBcAb negative recurrence were late recurrence (p=0.004). Positive HBcAb may represent a more invasive phenotype of HBV-related HCC, and is associated with a higher risk of early intrahepatic recurrence and poorer RFS of HBV-related patients after curative resection. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 06/2015; DOI:10.1111/liv.12898 · 4.85 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide, is a disease of immune microenvironment. Chronic Hepatitis B virus (HBV) infection, also an immune-related disease, is the major etiological factor for HCC especially in Asia. As an immune regulator, which has pleiotropic activities on T cells, nature killer cells and dendritic cells and so on, the efficacy of thymalfasin on HCC patients has been proven by several pilot studies as an adjuvant therapy. Combination of thymalfasin significantly improved survival and prolonged the time to tumor recurrence in patients who received transcatheter arterial chemoembolization after tumor resection. An improvement in patients' immunity has also been demonstrated. However, there is no large-scale randomized controlled study so far in resectable HCC patients. To confirm the role of thymalfasin adjuvant therapy in patients with HBV-related HCC after curative resection, a large-scale multicenter randomized controlled trial has been planned in China to investigate the effect of thymalfasin (1.6 mg twice a week for 12 months) on 2-year recurrence-free survival rate and tumor immune microenvironment. Here is the first announcement of the study protocol (ClinialTrials.gov Identifier: NCT02281266).
    Expert opinion on biological therapy 06/2015; 15(S1):1-5. DOI:10.1517/14712598.2015.1039979 · 3.74 Impact Factor
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    ABSTRACT: Lysyl oxidase like 4 (LOXL4), a member of the secreted copper-dependent amine oxidases that contribute to the assemble and maintenance of the extracellular matrix (ECM), was found to be up-regulated or down-regulated in different cancer types, suggesting its paradoxical roles in cancer. The specific role of LOXL4 in hepatocellular carcinoma (HCC), however, is still yet to be defined. Twenty-eight pairs of HCC specimens were used for LOXL4 mRNA expression analysis. The mRNA expression in HCC cell lines was examined, and HepG2 was selected for LOXL4 small interfering RNA (siRNA) interference to investigate the biological function of LOXL4, LOXL4 immunohistochemical staining was performed using a tissue microarray containing 298 HCC patients. The prognostic and diagnostic value of LOXL4 was evaluated using Cox regression and Kaplan-Meier analysis. LOXL4 mRNA or protein expression was significantly lower in HCC tissues than peritumoral tissues (LOXL4 mRNA expression, P = 0.018; LOXL4 protein expression, P < 0.001). Low LOXL4 expression was associated with lower overall survival (OS) rates and higher cumulative recurrence rates. Multivariate analysis indicated that LOXL4 was an independent prognostic indicator for OS and time to recurrence (TTR). Our results revealed that LOXL4 was down-regulated in HCC and correlated with aggressive tumors and a worse clinical outcome. LOXL4 may be a potential biomarker to identify the HCC patients with a higher risk of recurrence.
    International journal of clinical and experimental pathology 06/2015; 8(4):3892-3900. · 1.89 Impact Factor
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    ABSTRACT: Tumor cells with stemness (stem-cell) features contribute to initiation and progression of hepatocellular carcinoma (HCC), but the involvement of long noncoding RNAs (lncRNAs) remains largely unclear. Genome-wide analyses were applied to identify tumor-associated lncRNA-DANCR. The DANCR expression level and the prognostic values of DANCR were assayed in two HCC cohorts (China and Korea, n = 135 and 223). Artificial modulation of DANCR (down- and over-expression) was done to explore the role of DANCR in tumorigenesis and colonization and tumor-bearing mice were used to determine the therapeutic effects. We found that lncRNA-DANCR is over-expressed in stem-like HCC cells and this can serve as a prognostic biomarker for HCC patients. Experiments showed that DANCR markedly increased stemness features of HCC cells to promote tumorigenesis and intra-/extra-hepatic tumor colonization. Conversely, DANCR knock-down attenuated the stem-cell properties and in vivo interference with DANCR action led to decreased tumor cell vitality, tumor shrinkage and improved mouse survival. Additionally, we found that the role of DANCR relied largely on association with and regulation of CTNNB1. Association of DANCR with CTNNB1 blocked the repressing effect of miR-214, miR-320a and miR-199a on CTNNB1. This observation was confirmed in vivo, suggesting a novel mechanism of tumorigenesis involving lncRNAs, mRNAs and microRNAs. Our studies reveal a significance and mechanism of DANCR action in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HCC. This article is protected by copyright. All rights reserved. © 2015 by the American Association for the Study of Liver Diseases.
    Hepatology 05/2015; DOI:10.1002/hep.27893 · 11.06 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is the third most lethal cancer worldwide. Understanding the molecular pathogenesis of HCC recurrence and metastasis is the key to improve patients' prognosis. In this study, we report that protein tyrosine phosphatase receptor S (PTPRS) is significantly downregulated in nearly 80% of HCCs, and its expression negatively correlates with aggressive pathological features, like larger tumor size and advanced stage. In addition, PTPRS deficiency is independently associated with shorter survival and increased recurrence in patients, although 16.7% of HCCs show intratumor heterogeneous expression of PTPRS. Restoration of wild-type but not mutant PTPRS expression significantly inhibits HCC cell migration and invasion in vitro as well as lung metastasis in vivo, while knockdown of its expression significantly promotes invasion and metastasis. Notably, PTPRS-regulated HCC invasiveness is accompanied by typical changes of epithelial-mesenchymal transition. Moreover, PTPRS forms a complex with epithermal growth factor receptor (EGFR) and regulates its tyrosine residues' phosphorylation. Ectopic expression of EGFR reverses the metastasis inhibiting effects of PTPRS, whereas silencing of EGFR or inhibiting phosphorylation of key molecules in EGFR downstream pathways re-inhibits EMT and metastasis caused by PTPRS downregulation. Meanwhile, promoter hypermethylation of PTPRS is frequently detected in HCC samples and cell lines. Treatment with a de-methylation agent 5-Aza-CdR recovers PTPRS expression in a dose-dependent manner. These findings suggest that epigenetic inactivation of PTPRS may increase the phosphorylation and activity of EGFR signaling to promote EMT and metastasis in HCC. This article is protected by copyright. All rights reserved. © 2015 by the American Association for the Study of Liver Diseases.
    Hepatology 05/2015; DOI:10.1002/hep.27911 · 11.06 Impact Factor
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    ABSTRACT: A possible association between multiple drug resistance 1 gene (MDR1) polymorphisms and the risk of developing hepatocellular carcinoma (HCC) is currently under debate, and evidence from various epidemiological studies has yielded controversial results. To derive a more precise estimation of the association between MDR1 polymorphisms and HCC risk, the present meta-analysis was performed. A total of 8 studies containing 11 cohorts with 4407 cases and 4436 controls were included by systematic literature search of EMBASE, PubMed, Web of Science, and CNKI. All polymorphisms were classified as mutant/wild-type alleles. In particular, the variation type, functional impact, and protein domain location of the polymorphisms were assessed and used as stratified indicators. The pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated to evaluate the association. Overall, our results suggested that the mutant alleles of the MDR1 gene were associated with a significantly increased risk for HCC under all genetic models (allelic model: OR = 1.28, 95 % CI = 1.20-1.36, P < 0.001; dominant model: OR = 1.27, 95 % CI = 1.16-1.38, P < 0.001; recessive model: OR = 1.59, 95 % CI = 1.36-1.85, P < 0.001). Furthermore, increased risks for HCC were also revealed in stratified analyses by ethnicity, sample size, and quality scores of cohorts as well as variation type, functional impact, and protein domain location of polymorphisms. In conclusion, the present meta-analysis suggested that the presence of MDR1 mutant alleles might be a risk factor for HCC.
    Tumor Biology 04/2015; DOI:10.1007/s13277-015-3407-1 · 3.61 Impact Factor
  • 04/2015; DOI:10.2217/hep.15.12
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    ABSTRACT: The elevated platelet-to-lymphocyte ratio (PLR), determined using an easy blood test based on platelet and lymphocyte counts, is reported to be a predictor of poor survival in patients with several cancers. The prognostic role of preoperative PLR in patients with intrahepatic cholangiocarcinoma (ICC) has, until now, been rarely investigated. The purpose of our study was to evaluate the prognostic significance of PLR in a large cohort of ICC patients after hepatic resection.We obtained data from 322 consecutive nonmetastatic ICC patients who underwent hepatectomy without preoperative therapy between 2005 and 2011. Clinicopathological parameters, including PLR, were evaluated. Overall survival (OS) and recurrence-free survival (RFS) were assessed using the Kaplan-Meier method. Using multivariate Cox regression models, the independent prognostic value of preoperative PLR was determined.Our results showed that PLR represents an independent adverse prognostic factor for OS and RFS in ICC patients using univariate and multivariate analyses. The optimal PLR cutoff value was 123 using receiver operating curve analyses. The 5-year OS and RFS rates after hepatectomy were 30.3% and 28.9% for the group with PLR 123 greater, compared with 46.2% and 39.4% for the group with PLR less than 123 (P = 0.0058 and 0.0153, respectively). In addition, high PLR values were associated with tumor size (P = 0.020).Our results suggest that preoperative PLR might represent a novel independent prognostic factor for OS and RFS in ICC patients with hepatic resection.
    Medicine 04/2015; 94(13):e574. DOI:10.1097/MD.0000000000000574 · 5.72 Impact Factor
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    ABSTRACT: Malic enzyme 1 (ME1) links the glycolytic and citric acid cycles and is important for NADPH production, glutamine metabolism, and lipogenesis. Recently, its deregulation has been implicated in the progression of various cancers. However, the role of ME1 in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we utilized short hairpin RNA-mediated gene silencing to investigate the biological effects of ME1 depletion in HCC and determined its prognostic significance in HCC. ME1 expression was examined by real-time (RT)-PCR and Western blot using five HCC cell lines and one normal liver cell line. We used polyethylenimine nanoparticles to deliver a short hairpin RNA to induce cessation of ME1 expression in HCC cells. Changes in NADPH production and reactive oxygen species (ROS) production were studied. Metastatic potentials of HCC cells were evaluated in vitro. Furthermore, we evaluated the protein level of ME1 in para-tumor and cancerous tissues of 65 HCC patients with detailed clinical, pathological, and clinical follow-up data. Patients' survivals were further assessed as well. Upregulated ME1 expression was observed in HCC cell lines. Downregulation of ME1 attenuated NADPH production and stimulated ROS production. Silencing ME1 was noted to inhibit migratory and invasive properties of HCC cells by inducing the E-cadherin expression and decreasing of N-cadherin and vimentin expression in a ROS-dependent pathway. Overexpression of ME1 was observed in a major fraction of HCC samples. Higher level of ME1 in tumors was significantly associated with reduced overall survival (Kaplan-Meier analysis, P = 0.024) and reduced progression-free survival (Kaplan-Meier analysis, P = 0.011). Inhibition of ME1 expression decreases HCC metastasis via suppression of epithelial-mesenchymal transition (EMT) processes in ROS-induced pathways. ME1 overexpression associates with unfavorable prognoses in patients with HCC, suggesting that ME1 is a poor prognostic predictor of hepatocellular carcinoma.
    Tumor Biology 03/2015; 36(8). DOI:10.1007/s13277-015-3306-5 · 3.61 Impact Factor

Publication Stats

7k Citations
1,621.90 Total Impact Points


  • 2001–2015
    • Fudan University
      • Institutes of Biomedical Sciences
      Shanghai, Shanghai Shi, China
  • 2012
    • University of Michigan
      • Life Sciences Institute
      Ann Arbor, MI, United States
  • 1998–2008
    • Shanghai Medical University
      • • Liver Cancer Institute
      • • Department of Radiology
      Shanghai, Shanghai Shi, China
  • 2003–2004
    • Zhongshan University
      Shanghai, Shanghai Shi, China