[show abstract][hide abstract] 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.
[show abstract][hide abstract] 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;).
[show abstract][hide abstract] 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.
[show abstract][hide abstract] 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
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Acute rejection (AR) of an organ transplant is a life-threatening complication. Currently, there are few diagnostic biomarkers suitable for clinical application. We aim to determine the potential of plasma microRNAs as biomarkers for AR. METHODS: Using rat orthotopic liver transplantation model and microarrays, we compared the difference in the spectrum and levels of microRNAs in both plasma and grafts between AR rats and control. AR-related plasma microRNAs were selected and validated using real-time quantification polymerase chain reaction. Plasma from AR rats with or without tacrolimus treatment was used for microRNA dynamic monitoring. To clarify the origin of AR-related plasma microRNAs, drug-induced liver damage rat model were performed and in situ hybridization was used to detect and localize the specific microRNA in allografts. RESULTS: We found that plasma miR-122, miR-192, and miR-146a was significantly up-regulated when AR occur (fold change>2; P<0.05) and the elevation could be repressed by immunosuppression. In liver injury rat model, up-regulated plasma miR-122 (fold change=22.126; P=0.002) and miR-192 (fold change=8.833; P<0.001) rather than miR-146a (fold change=1.181; P=0.594) were observed. Further study demonstrated that miR-146a was up-regulated by sixfold in microvesicles isolated from AR plasma, whereas miR-122 and miR-192 showed no distinct change. In situ hybridization revealed that the portal areas of the AR graft were brimming with lymphocytes, which showed highly intense staining for miR-146a. CONCLUSIONS: Our study provides the global fingerprint of plasma microRNAs in AR rats and suggests that plasma miR-122 and miR-192 reflect liver injury, whereas miR-146a may associate with cellular rejection.
[show abstract][hide abstract] ABSTRACT: Sensitive and specific detection of liver cirrhosis is an urgent need for optimal individualized management of disease activity. Substantial studies have identified circulation miRNAs as biomarkers for diverse diseases including chronic liver diseases. In this study, we investigated the plasma miRNA signature to serve as a potential diagnostic biomarker for silent liver cirrhosis.
A genome-wide miRNA microarray was first performed in 80 plasma specimens. Six candidate miRNAs were selected and then trained in CHB-related cirrhosis and controls by qPCR. A classifier, miR-106b and miR-181b, was validated finally in two independent cohorts including CHB-related silent cirrhosis and controls, as well as non-CHB-related cirrhosis and controls as validation sets, respectively.
A profile of 2 miRNAs (miR-106b and miR-181b) was identified as liver cirrhosis biomarkers irrespective of etiology. The classifier constructed by the two miRNAs provided a high diagnostic accuracy for cirrhosis (AUC = 0.882 for CHB-related cirrhosis in the training set, 0.774 for CHB-related silent cirrhosis in one validation set, and 0.915 for non-CHB-related cirrhosis in another validation set).
Our study demonstrated that the combined detection of miR-106b and miR-181b has a considerable clinical value to diagnose patients with liver cirrhosis, especially those at early stage.
PLoS ONE 01/2013; 8(6):e66577. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sorafenib has become the standard first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of sorafenib in advanced HCC patients and explore its true value for specific subgroups.
A computer-based systematic search from January 2005 to June 2011 with "sorafenib" and "advanced hepatocellular carcinoma" as search terms was performed for possible clinical trials. Hazard ratios (HR) and their 95% confidence intervals (CI) for overall survival (OS) and time to progression (TTP), rates of partial response (PR), rates of toxicity effects, and details of subgroup analysis were extracted. Meta-analyses were done using the software Review Manager (version 5.0).
Six trials with 1164 patients were included. Based on three randomized controlled trials, the pooled HR (sorafenib/placebo) was 0.66 for OS (95% CI: 0.56-0.78; P<0.00001) and 0.57 for TTP (95% CI: 0.47-0.68; P<0.00001). The pooled odds ratio (OR) for PR was 2.96 (95% CI: 0.96-9.15; P=0.06). For three single-arm trials, the pooled HR was 0.69 for OS (95% CI: 0.56-0.84; P=0.0002) and 0.64 for TTP (95% CI: 0.52-0.78; P<0.00001). The pooled OR for PR in three single-arm trials was 3.56 (95% CI: 1.22-10.39; P=0.02). Subgroup analysis indicated that sorafenib was less effective in patients with extrahepatic spread (with: P=0.13 vs without: P<0.0001), with normal alpha-fetoprotein level (AFP) (P=0.15 vs elevated: P=0.0006), and with elevated level of serum bilirubin (P=0.06 vs normal: P=0.0009). Sorafenib-based therapy significantly increased the risk of grade 3/4 hand-foot skin reaction, diarrhea, fatigue, and rash/desquamation.
Sorafenib-based therapy benefits advanced HCC patients. Meanwhile, sorafenib is less effective for patients with extrahepatic spread, with normal AFP level and with elevated level of bilirubin.
[show abstract][hide abstract] 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.).
[show abstract][hide abstract] 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.
[show abstract][hide abstract] ABSTRACT: An immune function assay has been proposed as a new strategy to monitor immunosuppression after organ transplantation. However, there are limited data regarding its role in liver transplant recipients with hepatocellular carcinoma (HCC). In this study, we sought to determine the utility of this functional assay in assessing the risk of infection, rejection, and tumor recurrence in liver transplant recipients.
Immune function was determined by ImmuKnow assay that measures the amount of adenosine triphosphate (ATP) produced by CD4 (+) T cells to monitor the global immune status in 342 whole blood samples from 105 liver transplant recipients. The association between ATP value and post-transplant tumor recurrence was evaluated in 60 HCC patients. The ATP value in predicting tumor recurrence in other independent cohort of 92 recipients with HCC was analyzed prospectively.
The mean ATP values of liver transplant recipients with infection (145.2 ± 87.0 ng/ml) or acute rejection (418.9 ± 169.5 ng/ml) were different from those with stable state (286.6 ± 143.9 ng/ml, P < 0.05). In recipients with HCC who developed recurrent tumors, the values were significantly lower than those without recurrence (137.8 ± 66.4 vs. 289 ± 133.9 ng/ml, P < 0.01); the optimal threshold value to predict post-transplant tumor recurrence was 175 ng/ml. Comparing with the patients in lower immune group (ATP ≤ 175 ng/ml), patients in the higher immune group (ATP > 175 ng/ml) experienced significantly better disease-free survival (P < 0.01). Multivariate Cox regression analysis showed the ATP value was an independent predictor of HCC recurrence.
The immune function assay has the potential to assess the risk of infection and rejection in liver transplantation and to predict post-transplant tumor recurrence in recipients with HCC.
Journal of Cancer Research and Clinical Oncology 08/2011; 137(10):1445-53. · 2.91 Impact Factor
[show abstract][hide abstract] 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. · 4.12 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective: The goal of this study is to investigate the effects of sorafenib on tumor growth, recurrence and metastasis after curative resection of liver cancer. Research methods: SMMC-7721 and HCCLM3 liver tumors, each with different metastatic potential and basal phosphorylated extracellular signal-regulated kinase (pERK) levels, were orthotopically implanted into 56 nude mice. Mice were divided into a treatment sub study and a prevention sub study. Results: In the treatment sub study, tumor volumes in the high pERK-expressing HCCLM3 model were 2.58 ? 0.83 and 0.38 ? 0.09 cm(3) without and with sorafenib, respectively (p < 0.001). The corresponding volumes in the low pERK-expressing SMMC-7721 model were 1.36 ? 0.24 and 0.24 ? 0.14 cm(3) (p < 0.001), respectively. Sorafenib inhibited HCCLM3 cell proliferation and decreased tumor angiogenesis, but did not inhibit proliferation in the SMMC-7721 model. In the prevention sub study, intrahepatic recurrent tumor volumes were 1.96 ? 0.45 and 0.18 ? 0.24 cm(3) (p < 0.001); lung metastasis frequencies were 100 and 0% (p = 0.005); and lifespans were 36 ? 3 and 46 ? 5 days (p = 0.002) in the control and sorafenib subgroups, respectively. Conclusions: Sorafenib inhibits tumor growth and prevents metastatic recurrence after resection of hepatocellular carcinoma in nude mice. The effect of sorafenib does not exclusively depend on high levels of pERK in tumors.
[show abstract][hide abstract] ABSTRACT: Recurrence prediction of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) present a great challenge because of a lack of biomarkers. Genetic variations play an important role in tumor development and metastasis.
Oligonucleotide microarrays were used to evaluate the genetic characteristics of tumor DNA in 30 HBV-related HCC patients who were underwent LT. Recurrence-related single-nucleotide polymorphism were selected, and their prognostic value was assessed and validated in two independent cohorts of HCC patients (N = 102 and N = 77), using pretransplant plasma circulating DNA. Prognostic significance was assessed by Kaplan-Meier survival estimates and log-rank tests. Multivariate analyses were performed to evaluate prognosis-related factors.
rs894151 and rs12438080 were significantly associated with recurrence (P = .003 and P = .004, respectively). Multivariate analyses demonstrated that the co-index of the 2 SNPs was an independent prognostic factor for recurrence (P = .040). Similar results were obtained in the third cohort (N = 77). Furthermore, for HCC patients (all the 3 cohorts) exceeding Milan criteria, the co-index was a prognostic factor for recurrence and survival (P<.001 and P = .002, respectively).
Our study demonstrated first that genetic variations of rs894151 and rs12438080 in pretransplant plasma circulating DNA are promising prognostic markers for tumor recurrence in HCC patients undergoing LT and identify a subgroup of patients who, despite having HCC exceeding Milan criteria, have a low risk of post-transplant recurrence.
PLoS ONE 01/2011; 6(10):e26003. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: A retrospective cohort study was conducted to investigate the effect of interferon-α (IFN-α) therapy after curative resection on survival and recurrence in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).
Of 568 HBV-related HCC patients who underwent curative resection, 101 patients received postoperative IFN-α therapy (5 million units three times every week for 18 months). Clinicopathological factors were compared between patients with postoperative IFN-α therapy or not. Risk factors for survival, early, and late recurrence (2 years as cut-off) were studied.
The median follow-up time was 53.3 months. There was no significant difference in clinicopathological factors between the two groups. Patients with postoperative IFN-α therapy had higher overall survival rates (hazards ratio (HR): 0.612, 95% confidence interval (CI): 0.422-0.889, P = 0.010). No significant difference in disease-free survival rates was detected between the two groups (HR: 0.786, 95% CI: 0.597-1.035, P = 0.086). Multivariate analysis revealed that postoperative IFN-α therapy was an independent factor for overall survival (HR: 0.611, 95% CI: 0.421-0.887, P = 0.010) and significantly reduced early recurrence (HR: 0.562, 95% CI: 0.375-0.840, P = 0.005).
IFN-α therapy after curative resection prevented early recurrence and improved overall survival of patients with HBV-related HCC.
Journal of Surgical Oncology 09/2010; 102(7):796-801. · 2.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: A retrospective cohort study was conducted to identify risk factors for recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative resection. A total of 317 patients who had received curative resection of pathologically proven small HCC (< or = 3 cm in diameter) were analyzed to ascertain the factors affecting recurrence. The median follow-up period was 33.7 months. Cumulative recurrence rates at 1, 3, and 5 years after resection were 23.5%, 49.5%, and 65.5%, respectively. Male sex, alpha-fetoprotein (AFP) > or = 400 ng/mL, HBV DNA level > or = 4 log(10) copies/mL, prolonged prothrombin time, tumor size > or = 2 cm, microvascular invasion, absence of capsular formation, moderate/poor tumor differentiation, and absence of postoperative interferon-alpha (IFN-alpha) treatment were associated with increased cumulative risk of HCC recurrence. By multivariate analysis, HBV DNA level > or = 4 log(10) copies/mL (P < 0.001, hazard ratio (HR) 2.110), AFP > or = 400 ng/mL (P = 0.011, HR 1.574), microvascular invasion (P < 0.001, HR 1.767), and postoperative IFN-alpha treatment (P = 0.022, HR 0.562) remained to be independently associated with HCC recurrence. Those contributing to late recurrence (>2 years) were older age and HBV DNA level > or = 4 log(10) copies/mL. Patients with persistent HBV DNA level > or = 4 log(10) copies/mL at resection and follow-up had the highest recurrence risk (P < 0.001, HR 4.129). HBV DNA level > or = 4 log(10) copies/mL at the time of resection was the most important risk factor for recurrence. Postoperative IFN-alpha treatment significantly decreased the recurrence risk after resection.
Journal of Gastrointestinal Surgery 07/2010; 14(7):1111-20. · 2.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: The optimum strategy, hepatic resection (HR) or liver transplantation (LT), for treatment of early hepatocellular carcinoma (HCC) associated with liver diseases of Child-Pugh A is far from established. The aim of this study was to compare and determine which strategy is optimal for HCC fulfilling the Milan criteria.
Consecutive data were collected in 1,018 HCC patients treated with HR and 89 HCC patients listed for LT (1 drop out for HCC progression) between January of 2003 and December of 2007.
The independent prognostic factors identified by multivariate analysis were tumor size-plus-number, microscopic venous invasion, and operation type (LT or HR). When tumor size-plus-number was < or =4 or microscopic venous invasion was absent, there was no significant difference in overall survival (OS) between the LT and HR group. When tumor size-plus-number was >4 or microscopic venous invasion was present, OS was higher in the LT group.
Since the pathological microscopic venous invasion was not easily available before operation which is limitation for widespread clinical use, thus in practice, we concluded that, for early HCC associated with Child-Pugh A cirrhosis, when tumor size-plus-number is >4, LT provides the best cure; when it is < or =4, HR remains the initial treatment of choice.
Journal of Cancer Research and Clinical Oncology 02/2010; 136(9):1453-60. · 2.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: The platinum-based chemotherapeutic agent oxaliplatin displays a wide range of antitumor activities. To date, no detailed data are available about the effects of oxaliplatin on hepatocellular carcinoma (HCC) cells. Herein, the anti-proliferation effects of oxaliplatin on HCCLM3 and Hep3B cells in vitro and in vivo are studied.
Cell viability was assessed by an MTT assay and apoptosis by flow cytometry and transmission electron microscopy. Apoptosis-related proteins in HCCLM3 cells were evaluated by microarray analysis, quantitative reverse transcriptase-PCR assay and western blotting. The effect of oxaliplatin was also studied in vivo using a xenograft model.
Oxaliplatin inhibited the growth of HCCLM3 and Hep3B cells. Using flow cytometry, transmission electron microscopy and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, we found that apoptosis was the main mechanism by which oxaliplatin inhibited tumor progression. Microarray analysis, quantitative reverse transcriptase-PCR and western blot analysis further demonstrated downregulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL and upregulation of the pro-apoptotic protein Bax during oxaliplatin-induced apoptosis.
The anti-proliferation effect of oxaliplatin in HCC cells is due to induction of apoptosis. Therefore, oxaliplatin may be an effective treatment for HCC and its use merits further in-depth investigation.
[show abstract][hide abstract] ABSTRACT: Immunosuppressive therapy after liver transplantation for hepatocellular carcinoma (HCC) is one of the major contributory factors for HCC recurrence and metastasis. Sirolimus, a potent immunosuppressant, has been reported to be an effective inhibitor in a variety of tumors. The present study is designed to explore whether sirolimus could block the growth and metastatic progression of HCC.
MHCC97H cells were used as targets to explore the effect of sirolimus on cell cycle progression, apoptosis, proliferation, and its antiangiogenic mechanism. LCI-D20, a highly metastatic model of human HCC in nude mice, was also used as the model tumor to explore the effect of sirolimus on tumor growth and metastatic progression.
In vitro, sirolimus induced cell cycle arrest at the G1 checkpoint and blocked proliferation of MHCC97H cells but did not induce apoptosis. In vivo, sirolimus prevented tumor growth and metastatic progression in LCI-D20. Intratumoral microvessel density and circulating levels of VEGF in tumor-bearing mice were also significantly reduced in sirolimus treatment group. Quantitative RT-PCR showed that sirolimus down-regulated the mRNA expression of VEGF and HIF-1a, but not of bFGF, and TGF-b in MHCC97H cells. Furthermore, western blot analysis confirmed that sirolimus also decreased expression of HIF-1a at protein level, in parallel with the down-regulation of the levels of VEGF protein excretion in a time-dependent manner as compared to untreated control cells following anoxia.
The immunosuppressive macrolide sirolimus prevents the growth and metastatic progression of HCC, and suppresses VEGF synthesis and secretion by downregulating HIF-1a expression. Sirolimus may be useful for clinical application in patients who received a liver transplant for HCC.
Journal of Cancer Research and Clinical Oncology 12/2008; 135(5):715-22. · 2.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the prognostic value of tumor-associated macrophages (TAM), individually or synergistically with CD45RO + memory T cells (T(M)), in hepatocellular carcinoma (HCC) patients following resection.
The infiltration of TAM and T(M) was assessed by immunohistochemistry in tissue microarray containing 302 HCC specimens. Correlations between TAM/T(M) infiltration and clinicopathologic features, disease-free survival (DFS) and overall survival (OS) were statistically analyzed.
High TAM infiltration was associated with both improved DFS (P = 0.0021) and OS (P = 0.0481). Multivariate analysis identified TAM infiltration as independent prognostic factor for DFS (P = 0.004) and OS (P = 0.049). A second analysis clarified the synergistic effect of TAM&T(M) infiltration for DFS (P = 0.004) and OS (P = 0.040).
Both TAM infiltration alone and concomitant infiltration of TAM&T(M) are associated with improved DFS/OS, suggesting that TAM could protect HCC patients from recurrence/metastasis and prolong survival by distinct mechanisms.
Journal of Cancer Research and Clinical Oncology 09/2008; 135(3):439-49. · 2.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: Novel therapeutic strategies are needed to prevent the tumor recurrence or metastasis after liver transplantation for hepatocellular carcinoma (HCC). This study was to investigate the effect of rapamycin, alone and in combination with sorafenib, on HCC in vivo.
Xenograft of a highly metastatic human HCC tumor (LCI-D20) was used to evaluate primary tumor growth and lung metastasis after treatment with rapamycin alone or in combination with sorafenib. Tumor cell proliferation was determined by Ki-67 immunostaining. To detect tumor cell apoptosis, the terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assay was used. Tumor angiogenesis was investigated by using a monoclonal anti-CD31 antibody. A vascular endothelial growth factor ELISA kit was used to measure vascular endothelial growth factor protein levels in the mice serum.
Rapamycin, alone and in combination with sorafenib, strongly inhibited primary tumor growth and lung metastases in LCI-D20 model. Furthermore, the combination therapy significantly enhanced the effect of antitumor on primary tumor growth compared with single treatment with either rapamycin (P < 0.001) or sorafenib (P < 0.001). Rapamycin alone inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Nevertheless, the combination therapy showed a significant inhibition of tumor cell proliferation (P < 0.05). Additionally, the combination therapy also further enhanced suppression of tumor cell angiogenesis compared with rapamycin treatment (P < 0.01). However, the induction of apoptosis in combination therapy group was not significantly higher than in the rapamycin-treated group (P > 0.05).
The combination therapy of rapamycin and sorafenib could be a new and promising therapeutic approach to the treatment of HCC and prevention of HCC recurrence after liver transplantation.
Clinical Cancer Research 08/2008; 14(16):5124-30. · 7.84 Impact Factor