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human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by β-catenin/TCF

CANCER SCIENCE 2008年第6期99卷 1139-1146页

作者： Torisu, Yuichi Watanabe, Akira Nonaka, Aya Midorikawa, Yutaka Makuuchi, Masatoshi Shimamura, Takahiro Sugimura, Haruhiko Niida, Atsushi Akiyama, Tetsu Iwanari, Hiroko Kodama, Tatsuhiko Zeniya, Mikio Aburatani, Hiroyuki Univ Tokyo Adv Sci & Technol Res Ctr Genome Sci Div Meguro Ku Tokyo 1538904 Japan Univ Tokyo Adv Sci & Technol Res Ctr Lab Syst Biol & Med Meguro Ku Tokyo 1538904 Japan Univ Tokyo Dept Surg Hepatobiliary Pancreat Surg Div Bunkyo Ku Tokyo 1138655 Japan Univ Tokyo Inst Mol & Cellular Biosci Lab Mol & Genet Informat Bunkyo Ku Tokyo 1130032 Japan Jikei Univ Sch Med Dept Internal Med Div Gastroenterol & HepatolMinato Ku Tokyo 1058471 Japan Teikyo Univ Sch Med Mizonokuchi Hosp Takatsu Ku Kanagawa 2138507 Japan Hamamatsu Univ Sch Med Dept Pathol 1 Higashi Ku Shizuoka 4313192 Japan Perseus Proteom Meguro Ku Tokyo 1530041 Japan

The Drosophila Notum gene, which is regulated by the Wingless pathway, encodes a secreted hydrolase that modifies heparan sulfate proteoglycans. In comparative analysis of the gene expression profiles in primary human hepatocellular carcinomas (HCC) and normal organs, we observed that the human ortholog of Drosophila Notum was overexpressed markedly in a subset of HCC, but expressed rarely in adult normal tissues. Immunoblotting confirmed the overexpression of NOTUM protein in 12 of 40 primary HCC cases (30%). High levels of NOTUM protein were significantly associated with intracellular (nuclear or cytoplasmic) accumulation of beta-catenin protein: all 10 HCC with high intracellular beta-catenin also had high NOTUM expression, whereas only 2 of 30 cases (6.7%) without intracellular beta-catenin had high NOTUM expression (P < 0.00001). NOTUM expression in HepG2 cells was downregulated significantly by induction of a dominant-negative mutant of TCF4, a beta-catenin partner. In vivo binding of the beta-catenin/TCF complex to the NOTUM promoter was demonstrated by chromatin immunoprecipitation in HepG2 and SW480 cells, where canonical Wnt signaling is activated constitutively. These findings provide evidence that NOTUM is a novel target of beta-catenin/TCF4 and is upregulated in Wnt/beta-catenin signaling-activated HCC.

关键词： Adult Aged Animals Antibodies Monoclonal Carcinoma Hepatocellular 成年人老年人动物抗体单克隆癌肝细胞基因表达调控肿瘤免疫法 beta Catenin Carcinoma Wnt Signaling Pathway PID Hepatocellular Cancer Heparan Sulfate Proteoglycans Dominant-Negative Mutation human-centered computing Monoclonal Antibodies Adults Cytoplasmic accumulation Chromatin Immunoprecipitation

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Regional infusion-radioembolization

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SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA 2008年第4期17卷 957-+页

作者： Dubel, Gregory J. Soares, Gregory M. Brown Univ Rhode Isl Hosp Dept Diagnost Imaging Warren Alpert Sch MedDiv Intervent Radiol Providence RI 02903 USA

Selective internal radiation therapy involves the intra-arterial delivery of radioactive beads to the tumor while minimizing closing to the adjacent organ. Because this technique invariably results in some degree of embolization, it has also been termed radioembolization. More than 8000 patients have been treated worldwide, with a large body of experience with primary hepatocellular carcinoma (HCC) and metastatic colorectal carcinoma (MCRC) and growing experience with other tumors (metastatic neuroendocrine, breast carcinoma, cholangiocarcinoma). Response rates by FDG-PET are 80% to 90%. Complications are uncommon and most often consist of self-limited malaise. More significant complications, including radiation-induced liver disease, ischemic cholecystitis, and gastrointestinal ulceration may be seen in up to 10% of patients. This underscores the critical importance of patient selection and meticulous technique. Median survival times in patients who have HCC and MCRC are significantly improved compared with historic controls. Further study is required to determine the appropriate role of radioembolization in the context of state-of-the-art chemotherapy and other liver-directed therapies.

关键词： Chemoembolization Therapeutic Chemotherapy Cancer Regional Perfusion 化学栓塞治疗性肿瘤放射性药物放射疗法钇放射性同位素 chemoembolization selective internal radiation therapy Cancer Patient Selection Antineoplastic Agents isolated perfusion human-centered computing Drug Therapy

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Involvement of protein kinase C β-extracellular signal-regulating kinase_1/2/p38 mitogen-activated protein kinase-heat shock protein 27 activation in hepatocellular carcinoma cell motility and invasion

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CANCER SCIENCE 2008年第3期99卷 486-496页

作者： Guo, Kun Liu, Yinkun Zhou, Haijun Dai, Zhi Zhang, Jubo Sun, Ruixia Chen, Jie Sun, Qianglin Lu, Wenjing Kang, Xiaonan Chen, Pei Fudan Univ Zhongshan Hosp Liver Canc Inst Shanghai 200032 Peoples R China Fudan Univ Inst Biomed Sci Shanghai 200032 Peoples R China

To understand the molecular mechanism that underlies the role of various prominent signal pathways in hepatocellular carcinoma (HCC) metastasis, a human signal transduction oligonucleotide microarray analysis was carried out in cultured HCC cell models with increasing spontaneous metastatic potential (MHCC97L, MHCC97H, and HCCLM6). The results revealed that the mitogen-activated protein kinase (MAPK) pathway is the prominently upregulated pathway in HCC metastasis. Further study showed that basal phosphorylated levels of extracellular signal-regulating kinase (ERK)(1/2) and p38 MAPK consecutively increased from MHCC97L to MHCC97H to HCCLM6 cells, but not c-Jun N-terminal kinase. The phosphorylation of ERK1/2 and p38 MAPK was regulated by upregulated protein kinase C beta (PKC beta) in HCC cells through the integrated use of PKC beta RNA interference, the PKC beta specific inhibitor enzastaurin and a PKC activator phorbol-12-myristate-13-acetate. Heat shock protein 27 (HSP27) was also verified as a downstream common activated protein of PKC beta-ERK1/2 and PKC beta-p38 MAPK. In vitro migration and invasion assay further showed that the depletion of PKC beta or inhibition of PKC beta activation effectively decreased HCC cell motility and invasion. Moreover, the motility and invasion of phorbol-12-myristate-13-acetate-stimulated PKC beta-mediated HCC cells was significantly negated by an ERK inhibitor, 1.4-diamino-2.3-dicyano-1.4-bis[2-aminophenylthio] butadiene, or a p38 MAPK inhibitor, 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole. It also showed that HSP27 is critical in PKC beta-mediated HCC cell motility and invasion. Taken together, this study reveals the important role of this PKC beta-ERK1/2/p38MAPK-HSP27 pathway, which was verified for the first time, in modulating HCC cell motility and invasion.

关键词： Protein Kinase C Cell Movement activate mitogen-activated protein kinase p38 蛋白激酶C 细胞运动 Cell Locomotion Invasions Mitogen-Activated Protein Kinase p38 protein kinase C beta Protein Kinase C HSPB1 gene Protein Kinase C, Beta 1 Gene Mitogen-Activated Protein Kinases human-centered computing cell invasion

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Optimal amount of monocyte chemoattractant protein-1 enhances antitumor effects of suicide gene therapy against hepatocellular carcinoma by M1 macrophage activation

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CANCER SCIENCE 2008年第10期99卷 2075-2082页

作者： Tsuchiyama, Tomoya Nakamoto, Yasunari Sakai, Yoshio Mukaida, Naofumi Kaneko, Shuichi Kanazawa Univ Grad Sch Med Sci Kanazawa Ishikawa 9208641 Japan Kanazawa Univ Canc Res Inst Div Mol Bioregulat Kanazawa Ishikawa 9208641 Japan

Suicide gene therapy combined with chemokines provides significant antitumor efficacy. Coexpression of suicide gene and monocyte chemoattractant protein-1 (MCP-1) increases antitumor effects in murine models of hepatocellular carcinoma (HCC) and colon cancer. However, it is unclear whether the doses administered achieved the maximum antitumor effects. We evaluated antitumor effects of various amounts of recombinant adenovirus vector (rAd) expressing MCP-1 in the presence of a suicide gene in a murine model of HCC. HCC cells were transplanted subcutaneously into BALB/c nude mice, and transduced with a fixed amount of Ad-tk harboring the suicide gene, HSV-tk, and various doses of Ad-MCP1 harboring MCP-1 (ratios of 1:1, 0.1:1, and 0.01:1 relative to Ad-tk). Growth of primary tumors was suppressed when treated with Ad-tk plus Ad-MCP1 (1:1 and 1:0.1) as compared with Ad-tk alone. The antitumor effects against tumor rechallenge tended to be high in the Ad-tk plus Ad-MCP1 group (1:0.1). The effects were dependent on production of Th1 type-cytokines. Delivery of an optimal amount of rAd expressing MCP-1 enhanced the antitumor effects of suicide gene therapy against HCC by M1 macrophage activation, suggesting that this is a plausible form of cancer gene therapy to prevent HCC progression and recurrence. (Cancer Sci 2008;99: 2075-2082)

关键词： suicide gene therapy Hepatocellular Cancer roentgen equivalent man human-centered computing Monocyte chemoattractant protein-1 cancer gene therapy suicide gene Macrophage Activation

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Model for End-Stage Liver Disease (MELD) score system to evaluate patients with viral hepatitis on the waiting list: Better than the Child-Turcotte-Pugh (CTP) system?

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TRANSPLANTATION PROCEEDINGS 2008年第6期40卷 1906-1909页

作者： Cuomo, O. Perrella, A. Arenga, G. A Cardarelli Hosp AORN Hepat Surg & Liver Transplant Unit Dept Laparascop I-80131 Naples Italy

Background. The Model for End-Stage Liver Disease (MELD), based on creatinine, bilirubin, and International normalized ratio (INR), has been shown to be superior to the Child-Turcotte-Pugh (CTP) score in predicting 3-month mortality among patients on the transplant waiting list due to end-stage liver disease (ESLD). An additional advantage of MELD is the possibility to add "adjustment points" for exceptional patients at risk for death because of liver disease not identified by changes in the used parameters, as occurs in the case of hepatocellular carcinoma (HCC). Although it is useful, MELD has some important limitations: There are no differences for patients with or without ascites, and for the absence of other laboratory parameters involved in the etiology of disease. In this study, we evaluated dropouts of patients on the waiting list for orthotopic liver transplantation (OLT) based upon the characteristics of these subjects before and after introduction of the MELD score. Methods. All patients on the OLT waiting list from June 1, 2006 to June 30, 2007 were enrolled in the MELD group (A) and evaluated with CHILD and MELD score, while those listed from January 1, 2004 to May 31, 2005 were enrolled in pre-MELD group (13) to be evaluated with CHILD. In these subjects we assessed the drop out frequency and waiting time and we compared the results to assess possible differences (U Mann-Whitney Test;P < .05). Results. The total number of patients included in this study was 176: 116 patients in Group A and 60 in Group B. We had a drop-out frequency of 21% with a median of 9 +/- 6 S.E. months in Group A, while 9% with a median of 15 +/- 8 months S.E. in Group B. The dropout frequencies were as follows: Group A - 16 deaths (I HCC - 15 disease complications) while in Group B we had 13 drop outs, 10 exitus (4 HCC and 6 disease complications) and three exclusions for nonmedical reasons. In Group A we had a higher number of deaths due to disease complications than in group B

关键词： Group A Waiting Lists Child Group B rank Stage of Surgical Procedure 预约名单儿童 End Stage Liver Disease Waiting time Patients Liver Diseases Waiting Lists human-centered computing Viral Hepatitis cytidine triphosphate Child

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Natural history of chronic hepatitis B virus infection: What determines prognosis after cirrhotic decompensation?

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JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 2008年第11期23卷 1631-1632页

作者： Wei, Lai Peking Univ Hepatol Inst Peking Univ Peoples Hosp Beijing Peoples R China Peking Univ Peoples Hosp Inst Hepatol Beijing 100044 Peoples R China

See article in J. Gastroenterol. Hepatol. 2008;23: 1722-1727.

关键词： Infection as complication of medical care Hepatitis B virus measurement Natural history Prognosis Chronic Hepatitis B Disease Progression decompensation Liver Cirrhosis Hepatitis B virus Simian B disease Persons human-centered computing

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Radiofrequency-Assisted Liver Resection in Patients With Hepatocellular Carcinoma and Cirrhosis: Preliminary Results

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TRANSPLANTATION PROCEEDINGS 2008年第10期40卷 3523-3525页

作者： Curro, G. Habib, N. Jiao, L. Baccarani, U. Scisca, C. Navarra, G. Univ Hosp Messina Dept Surg Sci I-98100 Messina Italy Imperial Coll Sch Med Dept Surg Oncol & Technol London England Univ Udine Dept Surg & Transplantat I-33100 Udine Italy

Radiofrequency (RF)-assisted liver resection has been shown to allow virtually bloodless procedures without the need for vascular exclusion maneuvers. The aim of this study was to evaluate the safety and feasibility of RF-assisted liver resection in cirrhotic patients with hepatocellular carcinoma (HCC) and, moreover, to assess whether the RF-assisted procedure influenced the outcomes in terms of morbidity and mortality. This retrospective study included 39 cirrhotic patients who underwent RF-assisted liver resection for HCC between September 2001 and March 2006. In this period, we performed 17 monosegmentectomies, 16 bisegmentectomies, 4 trisegmentectomies, and 2 right hepatectomies. We never performed vascular exclusion maneuvers. Blood transfusion was necessary in 3 cases. One patient died postoperatively because of untreatable hepatorenal syndrome. The morbidity rate was 23%. Among patients without postoperative morbidity (n = 30), the 4-year survival rate was 61% versus 23% in patients who experienced postoperative morbidity (n = 9;P <.05). The 4-year disease-free survival rate was 40% in patients without postoperative morbidity versus 10% in patients who experienced postoperative morbidity (P =.05). Tumor dimension, number of lesions, and Child-Pugh class at surgery did not seem to significantly influence the 4-year overall survival (P >.05). In conclusion, RF-assisted liver resection was a safe, feasible procedure associated with low morbidity and hospital mortality rates even in cases of liver cirrhosis. It is, in our opinion, highly recommended for patients with HCC not suitable for liver transplantation.

关键词： Aged 80 and over Carcinoma Hepatocellular Female humans Liver Cirrhosis 老年人 80以上癌肝细胞肝硬化肝肿瘤无线电波回顾性研究 Patients Carcinoma Hepatocellular Cancer Hepatectomy Morbidity human-centered computing

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Cirrhotomimetic Type Hepatocellular Carcinoma Diagnosed After Liver Transplantation-Eighteen Months of Follow-up: A Case Report

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TRANSPLANTATION PROCEEDINGS 2008年第8期40卷 2835-2836页

作者： Han, Y. S. Choi, D. L. Park, J. B. Catholic Univ Daegu Sch Med Daegu Catholic Med Ctr Dept Surg Taegu 705718 South Korea Catholic Univ Daegu Sch Med Daegu Catholic Med Ctr Transplantat Ctr Taegu 705718 South Korea Catholic Univ Daegu Sch Med Daegu Catholic Med Ctr Dept Pathol Taegu 705718 South Korea

Diffuse-type hepatocellular carcinoma (HCC) is a contraindication to liver transplantation (OLT). However, cirrhotomimetic HCC, which is a form of the diffuse type, is difficult to diagnose preoperatively, there are no published reports about its prognosis after OLT. We performed an OLT for a case of cirrhotomimetic HCC diagnosed postoperatively. This 41-years-old man was on the waiting list for OLT owing to hepatitis B virus-related liver cirrhosis and esophageal variceal bleeding. Three months before transplantation, newly developed small nodules were detected on computed tomography (CT);there were no interval changes on CT after 2 months. His serum value of alpha-fetoprotein (alpha-FP) was 327 ng/mL. The patient received a deceased donor liver transplantation and his postoperative course was uneventful. However, on pathologic findings, the explanted liver showed malignant cells in most cirrhotic nodules. So, the patient's pathologic diagnosis was cirrhotomimetic HCC. Triple immunosuppression was administered and steroid stopped at about 2 weeks after transplantation. Eighteen months after transplantation, a-FP was 1.5 ng/mL and there was no evidence of recurrence on follow-up CT. In conclusion, cirrhotomimetic HCC is rare and difficult to detect, preoperatively. Despite the short-term follow-up, we did not detect recurrence of HCC.

关键词： month X-Ray Computed Tomography Transplantation of liver transplantation Hepatocellular Cancer Case Reports Medical Contraindication X-Ray Computed Tomography Transplantation Liver Transplantation Waiting Lists Optical Line Terminal human-centered computing Relapse

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Should the selection of children with hepatocellular carcinoma be based on Milan criteria?

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PEDIATRIC TRANSPLANTATION 2008年第1期12卷 1-3页

作者： Otte, Jean-Bernard Clin St Luc 10 Unite Chirurg Transplantat Hepat Pediat Brussels Belgium

In a recent issue of the Journal, Beaunoyer et al. (1) from Stanford University School of Medicine reported their experience with orthotopic liver transplantation (OLT) in 10 children with unre-sectable hepatocellular carcinoma (HCC). Selection was based on the Milan criteria (MC), which limits OLT to patients with one lesion > 5 cm in diameter or no more than three lesions, of which none should exceed 3 *** Network for Organ Sharing (UNOS) criteria for assigning the MELD/PELD scale scores are the same in adults and children. The use of the MC in the pediatric population restricts, at least in USA, the accessibility to OLT as most children present with large tumors exceeding 5 cm. The validity of this policy can be questioned as the experience with OLT in children with HCC is somewhat limited.

关键词： Carcinoma Hepatocellular humans Liver Neoplasms Liver Transplantation 癌肝细胞肝肿瘤肝移植病人选择治疗结果 experience Carcinoma Hepatocellular Cancer Liver Neoplasms human-centered computing Optical Line Terminal Liver Transplantation Child

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HCV histological recurrence and survival following liver transplantation in patients with and without hepatocellular carcinoma

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TRANSPLANTATION PROCEEDINGS 2008年第6期40卷 1974-1975页

作者： De Martin, E. Senzolo, M. Boninsegna, S. Guido, M. Masier, A. Germani, G. Tomat, S. Brolese, A. Neri, D. Cillo, U. Gambato, M. Russo, F. P. Farinati, F. Burra, P. Univ Padua Dept Surg Gastroenterol Sci Gastroenterol Padua Italy Univ Padua Inst Pathol Padua Italy

Background and aim. Hepatitis C virus (HCV)-related cirrhosis is one of the leading indication for liver transplantation (LT) and a major risk factor for the development of hepatocellular carcinoma (HCC). HCV recurrence after LT is universal. This study evaluated HCV recurrence and Survival in patients transplanted for HCV and HCC. Methods. We evaluated all adults transplanted for HCV cirrhosis between January 1999 and December 2006, HCC was diagnosed on the explant and HCV recurrence confirmed on protocol liver biopsies performed at 6 months and yearly after LT. The sustained viral response (SVR) was defined as HCV-RNA undetectable at 6 months after therapy discontinuation. The patient survival rates were assessed with Kaplan-Meier curves and the chi-square test was used when appropriate. Results. Two hundred sixteen patients underwent LT for HCV including 153 men and 63 women of mean age 54 years with a mean follow-up of 35 months. There were 71 (33%) HCC+ patients. At 1, 3, and 5 years from LT severe fibrosis (Scheuer 3-4) due to the HCV recurrence was reported in 18%, 14%, and 11% for HCC+ and 14%, 16%, and 28% for HCC- patients respectively (P = NS). HCC recurred only in 3 (4%) patients at a mean follow-up of 3 years. Patients who received antiviral treatment after LT were 10% HCC+ and 12% HCC- patients (P = NS). SVR was seen in 3/7 (43%) of HCC+ and in 10/18 (55%) of HCC- patients (P = NS). At 1, 3, and 5 years the patient survivals was 91%, 86%, and 86% for HCC+ and 94%, 86%, and 83% for HCC- patients, respectively (P = NS). Conclusions. Severe fibrosis due to HCV recurrence, which increases over time, involves one third of transplanted patients at 5 years after LT. The long-term survival was identical among HCC+ compared to HCC- recipients. The recurrence of HCC was negligible and did not affect patient survival.

关键词： Hepatitis C virus Recurrence Lymphotoxin survival aspects 复发淋巴毒素 Level Trigger Hepatocellular Cancer Risk Factors Lymphotoxin-alpha Peripheral Nervous System Survival Liver Transplantation human-centered computing Relapse Patients

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