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Differential Roles of Insulin-like Growth Factor Receptor- and Insulin Receptor-mediated Signaling in the Phenotypes of Hepatocellular Carcinoma Cells

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NEOPLASIA 2009年第9期11卷 835-U177页

作者： Chen, Ya-Wen Boyartchuk, Victor Lewis, Brian C. Univ Massachusetts Sch Med Program Gene Funct & Express Worcester MA 01605 USA Univ Massachusetts Sch Med Program Mol Med Worcester MA 01605 USA Univ Massachusetts Sch Med Ctr Canc Worcester MA 01605 USA

Intrahepatic and extrahepatic metastases are common findings in hepatocellular carcinoma (HCC). Insulin-like growth factor 2 (IGF2) expression is frequently induced in HCC, and serum IGF2 levels correlate with the presence of extrahepatic metastases. Yet, the role of IGF-induced signaling in the dissemination of HCC remains unclear. We have previously observed elevated IGF2 levels in tumors with metastatic potential in an HCC mouse model. Here, we demonstrate that inhibition of IGF2, or its receptor IGF1R, impairs the migration and invasion activities of murine HCC cells. Furthermore, inhibition of IGF1R also impairs the ability of HCC cells to colonize the lungs after introduction into the circulation through the tail vein but does not impair subcutaneous tumor growth. Collectively, these findings suggest that IGF1R-mediated signaling plays a causative role in tumor dissemination but is not required for tumor growth per se. Although previous studies indicate that IGF ligands can signal through IGF1R/insulin receptor (IR) heterodimers, and IR-A homodimers, we demonstrate that the IR is not required for invasion and metastasis by HCC cells. Finally, we identify matrix metalloproteinase 2 as a mediator of the invasive phenotype downstream of IGF1R-induced signaling. Thus, our studies demonstrate the importance of IGF2-induced signaling in the dissemination of HCC cells.

关键词： Phenotype Hepatocellular Cancer carcinoma cell metastasis Dissemination insulin-like growth factor II Matrix Metalloproteinase 2 tumor growth Growth Factor Receptors Caudal Vein Somatomedins human-centered computing

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Percutaneous Radiofrequency Ablation for Pulmonary Metastases from Hepatocellular Carcinoma: Results of a Multicenter Study in Japan

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JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 2011年第6期22卷 741-748页

作者： Hiraki, Takao Yamakado, Koichiro Ikeda, Osamu Matsuoka, Toshiyuki Kaminou, Toshio Yamagami, Takuji Gobara, Hideo Mimura, Hidefumi Kawanaka, Koichi Takeda, Kan Yamashita, Yasuyuki Inoue, Yuichi Ogawa, Toshihide Nishimura, Tsunehiko Kanazawa, Susumu Okayama Univ Sch Med Dept Radiol Okayama 7008558 Japan Mie Univ Sch Med Dept Radiol Tsu Mie 514 Japan Kumamoto Univ Grad Sch Med & Pharmaceut Sci Dept Diagnost Radiol Kumamoto Japan Osaka City Univ Grad Sch Med Dept Radiol Osaka 558 Japan Tottori Univ Dept Pathophysiol & Therapeut Sci Div Radiol Fac Med Tottori 680 Japan Kyoto Prefectural Univ Med Dept Radiol Grad Sch Med Sci Kyoto Japan

Purpose: To retrospectively evaluate technical success, effectiveness, complications, patient survival, and prognostic factors with percutaneous radiofrequency (RF) ablation for pulmonary metastases resulting from hepatocellular carcinoma (HCC). Materials and Methods: Thirty-two patients from six institutions were included, with a total of 83 pulmonary metastases treated in 65 sessions. RF ablation was always performed percutaneously with computed tomography (CT) guidance. Primary endpoints were technical success and technique effectiveness. Technique effectiveness was evaluated based on sequential follow-up CT images. Secondary study endpoints were complications, patient survival, and determination of prognostic factors. Complications were classified as major or minor. Prognostic factors were determined by analyzing multiple variables with the log-rank test. Results: Technical success rate was 100%. Primary technique effectiveness rates were 92% each at 1, 2, and 3 years. Major and minor complications occurred after 16 (25%) and 23 (35%) of the 65 sessions, respectively. The median follow-up period was 20.5 months. Overall survival rates were 87% at 1 year and 57% each at 2 and 3 years (median and mean survival times, 37.7 mo and 43.2 mo, respectively). Significantly better survival rates were obtained in cases of (i) no viable intrahepatic recurrence (P < .001), (ii) Child-Pugh class A disease (P < .001), (iii) absence of liver cirrhosis (P < .001), (iv) absence of hepatitis C virus infection (P = .006), and (v) alpha-fetoprotein level of 10 ng/mL or lower (P = .007) at the time of RF ablation. Conclusions: RF ablation appears effective, with an acceptable safety profile, in selected patients with pulmonary metastases resulting from HCC.

关键词： Hepatocellular Cancer End Point radiofrequency lung metastasis radiofrequency ablation Multicenter Study Japan human-centered computing

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Systems biology analysis of hepatitis C virus infection reveals the role of copy number increases in regions of chromosome 1q in hepatocellular carcinoma metabolism

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MOLECULAR BIOSYSTEMS 2016年第5期12卷 1496-1506页

作者： Elsemman, Ibrahim E. Mardinoglu, Adil Shoaie, Saeed Soliman, Taysir H. Nielsen, Jens Chalmers Univ Technol Dept Biol & Biol Engn S-41296 Gothenburg Sweden Assiut Univ Fac Sci Dept Math Assiut Egypt Tech Univ Denmark Novo Nordisk Fdn Ctr Biosustainabil Horsholm Denmark Royal Inst Technol Sci Life Lab Stockholm Sweden Assiut Univ Fac Comp & Informat Dept Informat Syst Assiut Egypt

Hepatitis C virus (HCV) infection is a worldwide healthcare problem;however, traditional treatment methods have failed to cure all patients, and HCV has developed resistance to new drugs. Systems biology-based analyses could play an important role in the holistic analysis of the impact of HCV on hepatocellular metabolism. Here, we integrated HCV assembly reactions with a genome-scale hepatocyte metabolic model to identify metabolic targets for HCV assembly and metabolic alterations that occur between different HCV progression states (cirrhosis, dysplastic nodule, and early and advanced hepatocellular carcinoma (HCC)) and healthy liver tissue. We found that diacylglycerolipids were essential for HCV assembly. In addition, the metabolism of keratan sulfate and chondroitin sulfate was significantly changed in the cirrhosis stage, whereas the metabolism of acyl-carnitine was significantly changed in the dysplastic nodule and early HCC stages. Our results explained the role of the upregulated expression of BCAT1, PLOD3 and six other methyltransferase genes involved in carnitine biosynthesis and S-adenosylmethionine metabolism in the early and advanced HCC stages. Moreover, GNPAT and BCAP31 expression was upregulated in the early and advanced HCC stages and could lead to increased acyl-CoA consumption. By integrating our results with copy number variation analyses, we observed that GNPAT, PPOX and five of the methyltransferase genes (ASH1L, METTL13, SMYD2, TARBP1 and SMYD3), which are all located on chromosome 1q, had increased copy numbers in the cancer samples relative to the normal samples. Finally, we confirmed our predictions with the results of metabolomics studies and proposed that inhibiting the identified targets has the potential to provide an effective treatment strategy for HCV-associated liver disorders.

关键词： Keratan Sulfate Chronic Hepatitis C liver tissue Liver Diseases Hepatitis C virus Chromosome 1 Long Arm human-centered computing Metabolism

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Reduced Efficacy of the Plk1 Inhibitor BI 2536 on the Progression of Hepatocellular Carcinoma due to Low Intratumoral Drug Levels

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NEOPLASIA 2012年第5期14卷 410-+页

作者： Haupenthal, Jorg Bihrer, Verena Korkusuz, Huedayi Kollmar, Otto Schmithals, Christian Kriener, Susanne Engels, Knut Pleli, Thomas Benz, Alexander Canamero, Marta Longerich, Thomas Kronenberger, Bernd Richter, Swantje Waidmann, Oliver Vogl, Thomas J. Zeuzem, Stefan Piiper, Albrecht Goethe Univ Frankfurt Dept Med 1 D-60590 Frankfurt Germany Goethe Univ Frankfurt Dept Diagnost & Intervent Radiol D-60590 Frankfurt Germany Univ Saarland Dept Gen Visceral Vasc & Pediat Surg D-6650 Homburg Germany Goethe Univ Frankfurt Dept Pathol D-60590 Frankfurt Germany Ctr Nacl Invest Oncol Comparat Pathol Unit Madrid Spain Heidelberg Univ Inst Pathol D-6900 Heidelberg Germany Univ Frankfurt M Inst Biostat & Math Modelling Frankfurt Germany

Highly promising preclinical data obtained in cultured cells and in nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In the present study, we investigated if Plk1 might be a suitable target in hepatocellular carcinoma (HCC) and if a genetically engineered mouse tumor model that well reflects the tumor cell and microenvironmental features of naturally occurring cancers might be suitable to study anti-Plk1 therapy. Analysis of Plk1 expression in human HCC samples confirmed that HCC express much higher Plk1 levels than the adjacent normal liver tissue. Inhibition of Plk1 by an adenovirus encoding for a short hairpin RNA against Plk1 or by the small-molecule inhibitor BI 2536 reduced the viability of HCC cell lines and inhibited HCC xenograft progression in nude mice. Treatment of transforming growth factor (TGF) alpha/c-myc bitransgenic mice with BI 2536 during hepatocarcinogenesis reduced the number of dysplastic foci and of Ki-67-positive cells within the foci, indicating diminished tumorigenesis. In contrast, BI 2536 had no significant effect on HCC progression in the transgenic mouse HCC model as revealed by magnetic resonance imaging. Measurement of BI 2536 by mass spectrometry revealed considerably lower BI 2536 levels in HCC compared with the adjacent normal liver tissue. In conclusion, low intratumoral levels are a novel mechanism of resistance to the Plk1 inhibitor BI 2536. Plk1 inhibitors achieving sufficient intratumoral levels are highly promising in HCC treatment. Neoplasia (2012) 14, 410-419

关键词： Hepatocellular Cancer progressions Nude Mice BI 2536 Neoplastic Cell human-centered computing

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Diet-induced hepatocellular carcinoma in genetically predisposed mice

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human MOLECULAR GENETICS 2009年第16期18卷 2975-2988页

作者： Hill-Baskin, Annie E. Markiewski, Maciej M. Buchner, David A. Shao, Haifeng DeSantis, David Hsiao, Gene Subramaniam, Shankar Berger, Nathan A. Croniger, Colleen Lambris, John D. Nadeau, Joseph H. Case Western Reserve Univ Dept Genet Sch Med Cleveland OH 44106 USA Univ Penn Dept Pathol & Lab Med Philadelphia PA 19104 USA Case Western Reserve Univ Dept Nutr Sch Med Cleveland OH 44106 USA Univ Calif San Diego Dept Bioengn San Diego CA 93093 USA Case Western Reserve Univ Sch Med Case Ctr Transdisciplinary Res Energet & Canc Cleveland OH 44106 USA Case Western Reserve Univ Sch Med Case Comprehens Canc Ctr Cleveland OH 44106 USA

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, with similar to 70% of cases resulting from hepatitis B and C viral infections, aflatoxin exposure, chronic alcohol use or genetic liver diseases. The remaining similar to 30% of cases are associated with obesity, type 2 diabetes and related metabolic diseases, although a direct link between these pathologies and HCCs has not been established. We tested the long-term effects of high-fat and low-fat diets on males of two inbred strains of mice and discovered that C57BL/6J but not A/J males were susceptible to non-alcoholic steatohepatitis (NASH) and HCC on a high-fat but not low-fat diet. This strain-diet interaction represents an important model for genetically controlled, diet-induced HCC. Susceptible mice showed morphological characteristics of NASH (steatosis, hepatitis, fibrosis and cirrhosis), dysplasia and HCC. mRNA profiles of HCCs versus tumor-free liver showed involvement of two signaling networks, one centered on Myc and the other on NF kappa B, similar to signaling described for the two major classes of HCC in humans. miRNA profiles revealed dramatically increased expression of a cluster of miRNAs on the X chromosome without amplification of the chromosomal segment. A switch from high-fat to low-fat diet reversed these outcomes, with switched C57BL/6J males being lean rather than obese and without evidence for NASH or HCCs at the end of the study. A similar diet modification may have important implications for prevention of HCCs in humans.

关键词： MicroRNAs Inbred Strain of Mice X Chromosome Metabolic Diseases Fat-Restricted Diet High-Fat Diet Obesity Dietary Modification human-centered computing

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Nanoparticle-formulated siRNA targeting integrins inhibits hepatocellular carcinoma progression in mice

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NATURE COMMUNICATIONS 2014年第May期5卷 3869-3882页

作者： Bogorad, Roman L. Yin, Hao Zeigerer, Anja Nonaka, Hidenori Ruda, Vera M. Zerial, Marino Anderson, Daniel G. Koteliansky, Victor MIT David H Koch Inst Integrat Canc Res Cambridge MA 02139 USA Max Planck Inst Mol Cell Biol & Genet D-01307 Dresden Germany MIT Dept Chem Engn Cambridge MA 02139 USA Harvard MIT Div Hlth Sci & Technol Cambridge MA 02139 USA MIT Inst Med Engn & Sci Cambridge MA 02139 USA Skolkovo Inst Sci & Technol Skolkovo 143025 Russia

Integrins play an important role during development, regulating cell differentiation, proliferation and survival. Here we show that knockdown of integrin subunits slows down the progression of hepatocellular carcinoma (HCC). Using nanoparticulate delivery of short interfering RNAs targeting beta 1 and alpha v integrin subunits, we downregulate all integrin receptors in hepatocytes. Short-term integrin knockdown (2 weeks) does not cause apparent structural or functional perturbations of normal liver tissue. Alterations in liver morphology accumulate on sustained integrin downregulation (7 weeks). The integrin knockdown leads to significant retardation of HCC progression, reducing proliferation and increasing tumour cell death. This tumour retardation is accompanied by reduced activation of the MET oncogene as well as expression of its mature form on the cell surface. Our data suggest that transformed proliferating cells from HCC are more sensitive to knockdown of integrins than normal quiescent hepatocytes, highlighting the potential of small interfering RNA-mediated inhibition of integrins as an anti-cancer therapeutic approach.

关键词： Integrins progressions MET gene integrin receptor Cell Surface human-centered computing

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Time to Transplantation as a Predictor of Hepatocellular Carcinoma Recurrence After Liver Transplantation

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LIVER TRANSPLANTATION 2014年第8期20卷 937-944页

作者： Samoylova, Mariya L. Dodge, Jennifer L. Yao, Francis Y. Roberts, John Paul Univ Calif San Francisco Dept Surg Div Transplant Surg San Francisco CA 94143 USA Univ Calif San Francisco Dept Med Div Gastroenterol San Francisco CA 94143 USA

In the United States, there are significant geographic disparities in the time to transplantation for patients with hepatocellular carcinoma (HCC);it is possible that rapid transplantation contributes to higher rates of posttransplant HCC recurrence because there is insufficient time for the tumor biology to manifest. In this study, we compared HCC recurrence in rapid transplant patients and their slower transplant counterparts. We identified adult liver transplantation (LT) candidates in the Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) data set who were granted an initial exception for an HCC diagnosis between January 1, 2006 and September 30, 2010 and underwent transplantation in the same time window. Patients were followed until HCC recurrence, non-HCC-related death, or last follow-up. The cumulative incidence of HCC recurrence was compared for patients waiting <= 120 days and patients waiting >120 days from an HCC exception to LT. The association between the risk of posttransplant recurrence and the wait time was further evaluated via competing risks regression with the Fine and Gray model. For 5002 LT recipients with HCC, the median wait time from an exception to LT was 77 days, and it varied from 30 to 169 days by UNOS region. The cumulative incidence of posttransplant HCC recurrence was 3.3% [95% confidence interval (CI) = 2.8%-3.8%] and 5.6% (95% CI = 5.0%-6.3%) within 1 and 2 years, respectively. The rate of observed recurrence within 1 year of transplantation was significantly lower for patients waiting >120 days versus patients waiting <= 120 days (2.2% versus 3.9%, P = 0.002);however, the difference did not persist at 2 years (5.0% versus 5.9%, P = 0.09). After we accounted for clinical factors, the HCC recurrence risk was reduced by 40% for patients waiting >120 days (subhazard ratio = 0.6, P = 0.005). In conclusion, the risk of HCC recurrence within the first year after transplantation may be lessened by the ins

关键词： AFP alpha-fetoprotein CI confidence interval DDLT deceased donor liver transplantation HCC hepatocellular carcinoma IQR interquartile range LDLT living donor liver transplantation LT liver transplantation MELD Model for End- Stage Liver Disease SHR subhazard ratio UNOS United Network for Organ Sharing. AFP alpha-Fetoproteins Confidence intervals Interquartile range Organ Procurement Waiting time IQR Hepatocellular Cancer Relapse human-centered computing Level Trigger Transplantation Liver Transplantation

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Multicentre study of the prognostic impact of preoperative bodyweight on long-term prognosis of hepatocellular carcinoma

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BRITISH JOURNAL OF SURGERY 2019年第3期106卷 276-285页

作者： Yu, J. J. Shen, F. Chen, T. H. Liang, L. Han, J. Xing, H. Zhou, Y. H. Wang, H. Gu, W. M. Lau, W. Y. Yang, T. Second Mil Med Univ Eastern Hepatobiliary Surg Hosp Dept Hepatobiliary Surg 225 Changhai Rd Shanghai 200438 Peoples R China Second Mil Med Univ Dept Clin Med Shanghai Peoples R China Ziyang First Peoples Hosp Dept Gen Surg Ziyang Sichuan Peoples R China Puer Peoples Hosp Dept Hepatobiliary Surg Puer Yunnan Peoples R China Liuyang Peoples Hosp Dept Gen Surg Liuyang Hunan Peoples R China Fourth Hosp Harbin Dept Gen Surg 1 Harbin Heilongjiang Peoples R China Chinese Univ Hong Kong Fac Med Shatin Hong Kong Peoples R China

Background: Whether preoperative bodyweight is associated with long-term prognosis in patients after liver resection for hepatocellular carcinoma (HCC) is controversial. This study aimed to investigate the relationship of patient weight with long-term recurrence and overall survival (OS) after curative liver resection for HCC. Methods: Data for patients with HCC who underwent curative liver resection between 2000 and 2015 in five centres in China were analysed retrospectively in three groups according to their preoperative BMI: underweight (BMI 18.4 kg/m(2) or less), normal weight (BMI 18.5-24.9 kg/m(2)) and overweight (BMI 25.0 kg/m(2) or above). Patients' baseline characteristics, operative variables and long-term survival outcomes were compared. Univariable and multivariable Cox regression analyses were performed to identify risk factors for OS and recurrence-free survival (RFS) after resection. Results: Of 1524 patients, 107 (7.0 per cent) were underweight, 891 (58.5 per cent) were of normal weight and 526 (34.5 per cent) were overweight. Univariable analyses showed that underweight and overweight patients had poorer OS (both P < 0.001) and RFS (both P < 0.001) than patients of normal weight. Multivariable Cox regression analysis also identified both underweight and overweight to be independent risk factors for OS (hazard ratio (HR) 1.22, 95 per cent c. i. 1.19 to 1.56, P = 0.019;and HR 1.57, 1.36 to 1.81, P < 0.001, respectively) and RFS (HR 1.28, 1.16 to 1.53, P = 0.028;and HR 1.34, 1.17 to 1.54, P < 0.001). Conclusion: Underweight and overweight patients appear to have a worse prognosis than those of normal weight following liver resection for HCC.

关键词： Hepatocellular Cancer Prognosis Multicenter Study Prognostic Hepatectomy human-centered computing

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Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma

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TARGETED ONCOLOGY 2017年第1期12卷 1-10页

作者： Swamy, Supritha G. Kameshwar, Vivek H. Shubha, Priya B. Looi, Chung Yeng Shanmugam, Muthu K. Arfuso, Frank Dharmarajan, Arunasalam Sethi, Gautam Shivananju, Nanjunda Swamy Bishayee, Anupam JSS Sci & Technol Univ Dept Biotechnol JSS Tech Inst Campus Mysore 570006 Karnataka India Univ Mysore Dept Studies Chem Mysore 570006 Karnataka India Univ Malaya Dept Pharmacol Fac Med Kuala Lumpur 50603 Malaysia Natl Univ Singapore Yong Loo Lin Sch Med Dept Pharmacol Singapore 117597 Singapore Curtin Univ Curtin Hlth Innovat Res Inst Sch Biomed Sci Biosci Res Precinct Bentley WA 6009 Australia Larkin Hlth Sci Inst Dept Pharmaceut Sci Coll Pharm 18301 N Miami Ave Miami FL 33169 USA

Hepatocellular carcinoma (HCC) is one of the most common forms of liver cancer diagnosed worldwide. HCC occurs due to chronic liver disease and is often diagnosed at advanced stages. Chemotherapeutic agents such as doxorubicin are currently used as first-line agents for HCC therapy, but these are non-selective cytotoxic molecules with significant side effects. Sorafenib, a multi-targeted tyrosine kinase inhibitor, is the only approved targeted drug for HCC patients. However, due to adverse side effects and limited efficacy, there is a need for the identification of novel pharmacological drugs beyond sorafenib. Several agents that target and inhibit various signaling pathways involved in HCC are currently being assessed for HCC treatment. In the present review article, we summarize the diverse signal transduction pathways responsible for initiation as well as progression of HCC and also the potential anticancer effects of selected targeted therapies that can be employed for HCC therapy.

关键词： Hepatocellular Cancer Signal Transduction Pathways protein tyrosine kinase inhibitor chronic liver disease Cancer of Liver sorafenib Side Effect human-centered computing

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RELATIONSHIP BETWEEN GENERAL OR SPECIFIC IMMUNOREACTIVITY AND PROGNOSIS IN POSTOPERATIVE-PATIENTS WITH HEPATOCELLULAR-CARCINOMA

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CANCER IMMUNOLOGY IMMUNOTHERAPY 1990年第2期31卷 107-114页

作者： YAMASAKI, H OKAMOTO, E KOMATSU, T MANABE, Y SHINKA, S HYOGO MED UNIV DEPT SURG 1 NISHINOMIYA HYOGO 663 JAPAN HYOGO MED UNIV DEPT IMMUNOL & MED ZOOL NISHINOMIYA HYOGO 663 JAPAN

The levels of a variety of immunological parameters were examined in 203 preoperative patients with hepatocellular carcinoma (HCC) at various stages (I-IV). The changes in the peripheral blood lymphocyte (PBL) count, the serum level of immunosuppressive acidic protein and the degree of the skin reaction to purified protein derivative were associated significantly with the stage of HCC progression. However, the percentages of lymphocyte subsets, mitogenic responsiveness of PBL and serum immunoglobulin concentration remained at the levels of stage I. Further study demonstrated that in patients undergoing hepatic artery ligation, there were statistically significant correlations between the PBL count, immunosuppressive acidic protein concentration and intensity of the skin reaction to purified protein derivative, assayed 1 month after surgery, and the prognosis. HCC-specific immunity was examined in 34 patients treated by hepatic resection or hepatic artery ligation using in vitro responses of PBL to HCC extracts (ATS test). This test was performed using culture medium containing added arginine. None of the PBL from the patients showed a positive response to allogeneic HCC extracts, but the PBL from 12 patients (9 hepatic resections, 3 hepatic artery ligations) were stimulated significantly (SI .gtoreq. 2.5) with autologous HCC extracts. In 7 of 9 hepatic resection patients who were positive in the ATS test, tumor recurrence was identified. Statistical analysis indicated that the ATS test result was significantly correlated with tumor recurrence in hepatic resection patients. Autologous-PBL-stimulating activities were isolated in a fraction at pH 8.3 and in fractions at pH 6.7-7.0 by chromatofocusing of the crude extract. Although identification of the HCC-specific antigen remains to be done, use of the above fractions may simplify the ATS test procedure and improve its sensitivity.

关键词： ATS SATELLITES Purified Protein Derivative of Tuberculin Hepatocellular Cancer Prognosis immunosuppressive acidic protein Fendiline Serum levels ectomy AUTOMATIC TRANSFER SWITCH Peripheral Blood Lymphocyte artery ligation fractions hepatic artery ligation human-centered computing Recurrent Neoplasm

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