Hou J.,Second Military Medical University |
Hou J.,Tsinghua University |
Lin L.,Zhejiang University |
Zhou W.,Eastern Hepatobiliary Surgery Hospital |
And 16 more authors.
Cancer Cell | Year: 2011
The full scale of human miRNome in specific cell or tissue, especially in cancers, remains to be determined. An in-depth analysis of miRNomes in human normal liver, hepatitis liver, and hepatocellular carcinoma (HCC) was carried out in this study. We found nine miRNAs accounted for ∼88.2% of the miRNome in human liver. The third most highly expressed miR-199a/b-3p is consistently decreased in HCC, and its decrement significantly correlates with poor survival of HCC patients. Moreover, miR-199a/b-3p can target tumor-promoting PAK4 to suppress HCC growth through inhibiting PAK4/Raf/MEK/ERK pathway both in vitro and in vivo. Our study provides miRNomes of human liver and HCC and contributes to better understanding of the important deregulated miRNAs in HCC and liver diseases. © 2011 Elsevier Inc.
Yin C.,Shanghai University |
Wang P.-Q.,Shanghai University |
Xu W.-P.,Shanghai University |
Yang Y.,Eastern Hepatobiliary Surgery Hospital |
And 7 more authors.
Hepatology | Year: 2013
Hepatocyte nuclear factor-4α (HNF4α) is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis. There is striking suppression of hepatocellular carcinoma (HCC) by HNF4α, although the mechanisms by which HNF4α reverses HCC malignancy are largely unknown. Herein, we demonstrate that HNF4α administration to HCC cells resulted in elevated levels of 28 mature microRNAs (miRNAs) from the miR-379-656 cluster, which is located in the delta-like 1 homolog (DLK1) -iodothyronine deiodinase 3 (DIO3) locus on human chromosome 14q32. Consistent with the reduction of HNF4α, these miRNAs were down-regulated in human HCC tissue. HNF4α regulated the transcription of the miR-379-656 cluster by directly binding to its response element in the DLK1-DIO3 region. Interestingly, several miRNAs in this cluster inhibited proliferation and metastasis of HCC cells in vitro. As a representative miRNA in this cluster, miR-134 exerted a dramatically suppressive effect on HCC malignancy by down-regulating the oncoprotein, KRAS. Moreover, miR-134 markedly diminished HCC tumorigenicity and displayed a significant antitumor effect in vivo. In addition, inhibition of endogenous miR-134 partially reversed the suppressive effects of HNF4α on KRAS expression and HCC malignancy. Furthermore, a positive correlation between HNF4α and miR-134 levels was observed during hepatocarcinogenesis in rats, and decreases in miR-134 levels were significantly associated with the aggressive behavior of human HCCs. Conclusion: Our data highlight the importance of the miR-379-656 cluster in the inhibitory effect of HNF4α on HCC, and suggest that regulation of the HNF4α-miRNA cascade may have beneficial effects in the treatment of HCC. © 2013 by the American Association for the Study of Liver Diseases.
Wang B.,Eastern Hepatobiliary Surgery Hospital |
Wang B.,Shanghai University |
Huang G.,Eastern Hepatobiliary Surgery Hospital |
Wang D.,Hebei Medical University |
And 5 more authors.
Journal of Hepatology | Year: 2010
Background & Aims: Studies investigating the associations between glutathione S-transferase (GST) genetic polymorphisms and hepatocellular carcinoma (HCC) risk have reported controversial results. Thus, a meta-analysis was performed to clarify the effects of GSTM1 and GSTT1 polymorphisms on HCC risk. Methods: We identified 132 relevant records through a literature search up to November 22, 2009, and 24 individual case-control studies from 23 publications were finally included, involving a total of 3349 HCC cases and 5609 controls. Subgroup analyses were performed by ethnicity, or by area according to the incidence rate and hepatitis virus status. Results: Analyses of total relevant studies showed an increased HCC risk was significantly associated with null genotypes of GSTM1 (OR = 1.26, 95% CI 1.03-1.54, pOR = 0.027) and GSTT1 (OR = 1.28, 95% CI 1.09-1.51, pOR = 0.002). In addition, the GSTM1-GSTT1 interaction analysis showed that the dual null genotype of GSTM1/GSTT1 was significantly associated with increased HCC risk (OR = 1.89, 95% CI 1.38-2.60, pOR < 0.001). Subgroup analyses showed that the associations above were still statistically significant in Asians (p GSTM1 = 0.017, pGSTT1 = 0.001, p Dual null genotype < 0.001), high-rate areas (pGSTM1 = 0.012, pGSTT1 = 0.006, pDual null genotype < 0.001), and HBV-dominant areas (pGSTM1 = 0.003, pGSTT 1 = 0.003, pDual null genotype < 0.001). Conclusions: This meta-analysis suggests null genotypes of GSTM1 and GSTT1 are both associated with increased HCC risk in Asians, and individuals with the dual null genotype of GSTM1/GSTT1 are particularly susceptible to developing HCC. © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Wang F.-S.,Beijing 302 Hospital |
Wang F.-S.,Zhejiang University |
Fan J.-G.,Shanghai JiaoTong University |
Zhang Z.,Beijing 302 Hospital |
And 2 more authors.
Hepatology | Year: 2014
Liver disease is a major cause of illness and death worldwide. In China alone, liver diseases, primarily viral hepatitis (predominantly hepatitis B virus [HBV]), nonalcoholic fatty liver disease, and alcoholic liver disease, affect approximately 300 million people. The establishment of the Expanded Program on Immunization in 1992 has resulted in a substantial decline in the number of newly HBV-infected patients; however, the number of patients with alcoholic and nonalcoholic fatty liver diseases is rising at an alarming rate. Liver cancer, one of the most deadly cancers, is the second-most common cancer in China. Approximately 383,000 people die from liver cancer every year in China, which accounts for 51% of the deaths from liver cancer worldwide. Over the past 10 years, China has made some significant efforts to shed its "leader in liver diseases" title by investing large amounts of money in funding research, vaccines, and drug development for liver diseases and by recruiting many Western-trained hepatologists and scientists. Over the last two decades, hepatologists and scientists in China have made significant improvements in liver disease prevention, diagnosis, management, and therapy. They have been very active in liver disease research, as shown by the dramatic increase in the number of publications in Hepatology. Nevertheless, many challenges remain that must be tackled collaboratively. In this review, we discuss the epidemiology and characteristics of liver diseases and liver-related research in China. © 2014 by the American Association for the Study of Liver Diseases.
Zheng L.-Y.,Changhai Hospital |
Zhou D.-X.,Eastern Hepatobiliary Surgery Hospital |
Lu J.,Changhai Hospital |
Zhang W.-J.,Changhai Hospital |
Zou D.-J.,Changhai Hospital
Biochemical and Biophysical Research Communications | Year: 2012
The protein-tyrosine phosphatase 1B (PTP1B) is a classical non-transmembrane protein tyrosine phosphatase that plays a key role in metabolic signaling and can exert both tumor suppressing and tumor promoting effects in different cancers depending on the substrate involved and the cellular context. However, the expression level and function of PTP1B in hepatocellular carcinoma (HCC) remain unclear. In this study, PTP1B expression was detected by immunohistochemistry in normal liver tissue (n=16) and hepatocellular carcinoma (n=169). The correlations between PTP1B expression level and clinicopathologic features and patient survival were also analyzed. One hundred and eleven of 169 HCC patients (65.7%) had negative or low PTP1B expression in tumorous tissues, whereas normal tissues always expressed strong PTP1B. Decreased PTP1B expression was significantly associated with aggressive clinicopathologic features and poor prognosis. Immunohistochemistry also showed that low PTP1B expression level was correlated with high percentage of OV6 + tumor-initiating cells (T-ICs) and high frequency of nuclear β-Catenin expression in HCC specimens. Our findings demonstrate for the first time that the loss of inhibitory effect of PTP1B may contribute to progression and invasion of HCC through activation of Wnt/β-Catenin signaling and expansion of liver T-ICs. PTP1B may serve as a valuable prognostic biomarker and potential therapeutic target in HCC. © 2012 Elsevier Inc.
Huang J.,China Pharmaceutical University |
Zhang H.,China Pharmaceutical University |
Yu Y.,China Pharmaceutical University |
Chen Y.,China Pharmaceutical University |
And 8 more authors.
Biomaterials | Year: 2014
To develop biodegradable docetaxel-loaded self-assembled nanoparticles of poly (d,l-lactide-co-glycolide)/hyaluronic acid block copolymers were successfully synthesized. These copolymers could form nanoparticles with small size (<200nm), an acceptable CMC (~7.9mg/L), typical core/shell structure and superior stability in one week. DTX-loaded PLGA502H-b-HA5.6k nanoparticles (DTX/SANPs) showed a biphasic release pattern within 120h, and exhibited enhanced cytotoxicity towardCD44-overexpressing MDA-MB-231 cells. Cellular uptake study indicated that PLGA502H-b-HA5.6k nanoparticles (SANPs) weretaken up in MDA-MB-231 cells by CD44-mediated endocytosis. Pharmacokinetics study revealed DTX/SANPs could prolong the circulation of DTX in the blood. Invivo studies demonstrated that SANPsexhibited enhanced tumor targeting and antitumor activity with lower systemic toxicity. In conclusion, DTX/SANPs have great potential for targeted chemotherapy for CD44-overexpressing breast cancer. © 2013 Elsevier Ltd.
Han Y.,Second Military Medical University |
Chen Z.,CAS Beijing National Laboratory for Molecular |
Yang Y.,Eastern Hepatobiliary Surgery Hospital |
Jiang Z.,Second Military Medical University |
And 9 more authors.
Hepatology | Year: 2014
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. HCC-induced immunosuppression often leads to ineffectiveness of immuno-promoting therapies. Currently, suppressing the suppressors has become the potential strategy for cancer immunotherapy. So, figuring out the immunosuppressive mechanisms induced and employed by HCC will be helpful to the design and application of HCC immunotherapy. Here, we identified one new subset of human CD14+CTLA-4+ regulatory dendritic cells (CD14+DCs) in HCC patients, representing ∼13% of peripheral blood mononuclear cells. CD14+DCs significantly suppress T-cell response in vitro through interleukin (IL)-10 and indoleamine-2,3-dioxygenase (IDO). Unexpectedly, CD14+DCs expressed high levels of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1, and CTLA-4 was found to be essential to IL-10 and IDO production. So, we identified a novel human tumor-induced regulatory DC subset, which suppresses antitumor immune response through CTLA-4-dependent IL-10 and IDO production, thus indicating the important role of nonregulatory T-cell-derived CTLA-4 in tumor-immune escape or immunosuppression. Conclusions: These data outline one mechanism for HCC to induce systemic immunosuppression by expanding CD14+DCs, which may contribute to HCC progression. This adds new insight to the mechanism for HCC-induced immunosuppression and may also provide a previously unrecognized target of immunotherapy for HCC. © 2013 by the American Association for the Study of Liver Diseases.
Huang G.,Eastern Hepatobiliary Surgery Hospital |
Lai E.C.H.,Eastern Hepatobiliary Surgery Hospital |
Lai E.C.H.,Chinese University of Hong Kong |
Lau W.Y.,Eastern Hepatobiliary Surgery Hospital |
And 6 more authors.
Annals of Surgery | Year: 2013
Objective:: This study aimed to clarify the incidence of hepatitis B virus (HBV) reactivation and its significance on long-term survival after partial hepatectomy in patients with HBV-related hepatocellular carcinoma (HCC), who had preoperative low HBV-DNA level of less than 2000 IU/mL. Background:: HBV reactivation is a frequent complication of systemic chemotherapy in hepatitis B surface antigen-positive patients. Surgery and anesthesia result in a generalized state of immunosuppression in the immediate postoperative period. Data on HBV reactivation and its significance after partial hepatectomy are unclear. PATIENTS AND METHODS:: Consecutive patients from January 2006 to December 2007 were retrospectively studied. RESULTS:: HBV reactivation happened in 19.1% of patients in 1 year. There were 28 patients whose HBV reactivation was detected after the diagnosis of HCC recurrence. On multivariate analysis, hepatitis B e antigen (HBeAg) positivity, preoperative HBV-DNA above the lower limit of quantification (≥200 IU/mL), Ishak inflammation score of greater than 3, preoperative transarterial chemoembolization (TACE), operation time of more than 180 minutes, blood transfusion, and without prophylactic antiviral therapy were significantly associated with an increased risk of HBV reactivation. HBV reactivation negatively influenced postoperative hepatic functions. The posthepatectomy liver failure rate in patients with HBV reactivation was significantly higher than in those without reactivation (11.8% vs 6.4%; P = 0.002). The 3-year disease-free survival (DFS) rate and overall survival (OS) rates after resection in patients with HBV reactivation were significantly lower than those without reactivation (34.1% vs 46.0%; P = 0.009, and 51.6% vs 67.2%; P < 0.001, respectively). HBeAg positivity, detectable preoperative HBV-DNA level, high Ishak inflammation score, preoperative TACE, long operation time, and blood transfusion were independent risk factors for HBV reactivation, whereas prophylactic antiviral therapy was a protective factor. HBV reactivation, HBeAg positivity, HBV-DNA level of 200 IU/mL or more, tumor diameter greater than 5 cm, presence of satellite nodules, presence of portal vein tumor thrombus, blood transfusion, and resection margin less than 1.0 cm were independent risk factors for DFS. A HBV-DNA level of 200 IU/mL or more, an Ishak fibrosis score of 4 or greater, a tumor diameter greater than 5 cm, the presence of satellite nodules, the presence of portal vein tumor thrombus, a resection margin less than 1.0 cm, no prophylactic antiviral therapy, and HBV reactivation were independent risk factors for OS. CONCLUSIONS:: HBV reactivation was common after partial hepatectomy for HBV-related HCC with a preoperative low HBV-DNA level of less than 2000 IU/mL. Routine prophylactic antiviral treatment should be given before partial hepatectomy. © 2013 by Lippincott Williams & Wilkins.
Wang Y.,Eastern Hepatobiliary Surgery Hospital |
Yuan L.,Eastern Hepatobiliary Surgery Hospital |
Ge R.-L.,Eastern Hepatobiliary Surgery Hospital |
Sun Y.,Eastern Hepatobiliary Surgery Hospital |
Wei G.,Eastern Hepatobiliary Surgery Hospital
Annals of Surgical Oncology | Year: 2013
Background: The significance of surgery in the treatment of hepatocellular carcinoma (HCC) extending into the inferior vena cava (IVC)/right atrium (RA) is currently unclear. We sought to clarify whether surgical treatment can improve survival in such patients. Methods: A retrospective review was undertaken of patients with HCC and IVC/RA tumor thrombus who were potential candidates for surgery but who were finally treated surgically and nonsurgically between September 2000 and October 2010. The patients were subdivided according to therapeutic modalities, and the results for each group were compared. Results: A total of 56 patients were included in this study. They were divided into three groups. Twenty-five patients underwent hepatectomy plus thrombectomy (surgical group), with minor morbidity and no mortality; the patients in this group had 1-, 3-, and 5-year survival rates of 68.0, 22.5, and 13.5 %, respectively, with a median survival of 19 months. Twenty patients were treated with transcatheter arterial chemoembolization, with 1- and 3-year survival rates of 15.0 and 5.0 %, respectively (median survival 4.5 months). Eleven patients received symptomatic treatment only, and no one in this group survived longer than 1 year (median survival 5 months). The patients in surgical group survived significantly longer than the patients in the other two groups (p < 0.001). Conclusions: Although technically challenging, surgery for HCC with IVC/RA tumor thrombus can be safely performed and should be considered in patients with resectable primary tumor and sufficient hepatic reservoir because compared with transcatheter arterial chemoembolization or symptomatic treatment, it significantly improved patient survival. © 2012 Society of Surgical Oncology.
Zhang Y.,Eastern Hepatobiliary Surgery Hospital |
Shi Z.-L.,Eastern Hepatobiliary Surgery Hospital |
Yang X.,Eastern Hepatobiliary Surgery Hospital |
Yin Z.-F.,Eastern Hepatobiliary Surgery Hospital
World Journal of Gastroenterology | Year: 2014
Currently, the main treatment for hepatocellular carcinoma (HCC) involves the surgical removal of tumors or liver transplantation. However, these treatments are often not completely curative, as they are associated with a risk for postoperative recurrence and metastasis. Circulating tumor cells (CTCs) are increasingly recognized as the main source for recurrence and metastasis after radical hepatectomies are performed. Many studies have demonstrated the association between the presence of either preor postoperative CTCs and an increased risk for HCC recurrence. To improve the therapeutic outcome of HCC, a personalized, comprehensive and multidisciplinary approach should be considered, involving the application of appropriate diagnostic and therapeutic measures targeting HCC CTCs in different stages throughout the course of treatment. This article proposes some HCC CTC-based strategies for the treatment of HCC, including the monitoring of HCC CTCs before, during and after radical hepatectomy, therapeutic targeting of HCC CTCs, prevention of the generation and colonization of CTCs, as well as the use of CTC indexes for the selection of indications, prediction of prognoses, and planning of individualized therapeutic regimens. Innovation and technological development of therapies targeting CTCs, as well as their translation into clinical practice, will help to effectively reduce postoperative recurrence and metastasis, and significantly prolong the survival of HCC patients. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.