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Overexpression of Long Non-coding RNA HOTAIR Predicts Tumor Recurrence in Hepatocellular Carcinoma Patients Following Liver Transplantation

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ANNALS OF SURGICAL ONCOLOGY 2011年第5期18卷 1243-1250页

作者： Yang, Zhe Zhou, Lin Wu, Li-Ming Lai, Ming-Chun Xie, Hai-Yang Zhang, Feng Zheng, Shu-Sen Minist Publ Hlth Key Lab Combined Multiorgan Transplantat Key Lab Organ Transplantat Hangzhou Zhejiang Peoples R China Zhejiang Univ Sch Med Div Hepatobiliary & Pancreat Surg Affiliated Hosp 1Dept Surg Hangzhou 310003 Zhejiang Peoples R China

The long noncoding RNA HOTAIR has been reported as a poor prognostic biomarker in patients with breast cancer. The aim of the present study is to examine the expression pattern of HOTAIR in hepatocellular carcinoma (HCC) and its clinical significance as well as its biological role in tumor progression. We examined the expression of HOTAIR in 110 HCC samples using real-time reverse transcription-polymerase chain reaction and analyzed its correlation with clinical parameters and prognosis in 60 HCC patients that have undergone liver transplantation (LT). Suppression of HOTAIR using siRNA was performed to explore its roles in tumor progression. The expression level of HOTAIR in cancer tissues was higher than in adjacent noncancerous tissues. High expression level of HOTAIR was an independent prognostic factor for predicting HCC recurrence in LT patients (P = .001, hazard ratio, 3.564). Furthermore, in patients exceeding the Milan criteria, those with a high expression level of HOTAIR revealed a significantly shorter recurrence-free survival. Moreover, siRNA suppression of HOTAIR in a liver cancer cell line reduced cell viability and cell invasion, sensitized TNF-alpha induced apoptosis, and increased the chemotherapeutic sensitivity of cancer cells to cisplatin and doxorubicin. The high expression level of HOTAIR in HCC could be a candidate biomarker for predicting tumor recurrence in HCC patients who have undergone liver transplant therapy and might be a potential therapeutic target.

关键词： Protein Overexpression cancer cell Liver Transplantation human-centered computing HOTAIR gene Recurrent Neoplasm liver cancer cell line

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Cyclin-dependent kinase inhibitor 3 (CDKN3) novel cell cycle computational network between human non-malignancy associated hepatitis/cirrhosis and hepatocellular carcinoma (HCC) transformation

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CELL PROLIFERATION 2011年第3期44卷 291-299页

作者： Wang, L. Sun, L. Huang, J. Jiang, M. Beijing Univ Posts & Telecommun Sch Elect Engn Biomed Ctr Beijing 100876 Peoples R China Tsinghua Univ Sch Humanities & Social Sci Lab Computat Linguist Beijing 100084 Peoples R China

The relationship of cyclin-dependent kinase inhibitor 3 (CDKN3) with tumours has previously been presented in a number of publications. However, the molecular network and interpretation of CDKN3 through the cell cycle between non-malignancy associated hepatitis/cirrhosis and hepatocellular carcinoma (HCC) have remained to be elucidated. Here, we have constructed and analysed significant high expression gene CDKN3 activated and inhibited cell cycle networks from 25 HCC versus 25 non-malignancy associated hepatitis/cirrhosis patients (viral infection HCV or HBV) in GEO Dataset GSE10140-10141, by combination of a gene regulatory network inference method based on linear programming, and decomposition procedure using CapitalBio MAS 3.0 software, based on integration of public databases including Gene Ontology, KEGG, BioCarta, GenMapp, Intact, UniGene, OMIM, and others. Comparing the same and differently activated and inhibited CDKN3 networks with GO analysis, between non-malignancy associated hepatitis/cirrhosis and HCC, our results suggest a CDKN3 cell cycle network (i) with stronger DNA replication and with weaker ubiquitin-dependent protein catabolism as common characteristics in both non-malignancy associated hepatitis/cirrhosis and HCC;(ii) with more cell division and weaker mitotic G2 checkpoint in non-malignancy associated hepatitis/cirrhosis;(iii) with stronger cell cycle and weaker cytokinesis, as a result forming multinucleate cells in HCC. Thus, it is useful to identify CDKN3 cell cycle networks for comprehension of molecular mechanism between non-malignancy associated hepatitis/cirrhosis and HCC transformation.

关键词： Cyclin-Dependent Kinase Inhibitor 3 Cell Cycle Cell Division protein degradation Giant Cells human-centered computing phosphotransferase inhibitor Network

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Treatment Strategy for Hepatocellular Carcinoma with Major Portal Vein or Inferior Vena Cava Invasion: A Single Institution Experience

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JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS 2011年第5期212卷 796-803页

作者： Yoshidome, Hiroyuki Takeuchi, Dan Kimura, Fumio Shimizu, Hiroaki Ohtsuka, Masayuki Kato, Atsushi Furukawa, Katsunori Yoshitomi, Hideyuki Miyazaki, Masaru Chiba Univ Grad Sch Med Dept Gen Surg Chuo Ku Chiba 2608670 Japan

BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) invading the main trunk of the portal vein and the inferior vena cava is dismal. The best strategy for treatment is not well known. STUDY DESIGN: We retrospectively reviewed the medical records of 641 patients treated for HCC between 1990 and June 2009. Eighty-four (13%) of these patients had HCC, with a tumor thrombus invading the main trunk or the first-order branch of the portal vein, or the inferior vena cava. Thirty-four patients underwent hepatectomy and 50 patients underwent transcatheter arterial chemoembolization (TACE). We specifically focused on these 34 patients to describe our results of surgical treatment for advanced HCC. RESULTS: Among the 34 patients who underwent hepatectomy, preoperative TACE was performed in 15 patients. Six patients were identified as having a tumor size reduction or necrosis of 50% or higher (TE3) by TACE. The median operative duration was 355 minutes. Postoperative morbidity and mortality rates were 44% and 2.9%, respectively. The 5-year survival rate after hepatectomy was 20%, which was better than that of patients after TACE alone. The response after preoperative TACE (hazard ratio 4.65;95% CI, 1.39 to 15.5) and tumor diameter (hazard ratio 2.78;95% CI, 1.16 to 6.64) were identified as significant favorable preoperative prognostic factors for survival using the multivariable Cox model. Patients with tumors smaller than 10 cm and TE3 effect had a more favorable survival than patients with tumors 10 cm or larger and who did not have a good TACE outcome. CONCLUSIONS: A combination of aggressive surgical treatment and effective preoperative TACE treatment for HCC with major vascular invasion may be beneficial for selected patients. (J Am Coll Surg 2011;212:796-803. (C) 2011 by the American College of Surgeons)

关键词： Venae Cavae ordered branch Transmission Lines Hepatectomy TE3 Hepatocellular Cancer Trunk of portal vein Operative Surgical Procedures Tumor thrombus Portal Vein human-centered computing Inferior Vena Cava Size reduction Patients

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Liver stiffness measurement by magnetic resonance elastography is not associated with developing hepatocellular carcinoma in subjects with compensated cirrhosis

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ALIMENTARY PHARMACOLOGY & THERAPEUTICS 2011年第1期34卷 83-91页

作者： Anaparthy, R. Talwalkar, J. A. Yin, M. Roberts, L. R. Fidler, J. L. Ehman, R. L. Mayo Clin Div Gastroenterol & Hepatol Rochester MN 55905 USA Mayo Clin Ctr Adv Imaging Res Rochester MN 55905 USA Mayo Clin Dept Radiol Rochester MN 55905 USA

Background Liver stiffness assessed using transient elastography is described as a potential risk factor for hepatocellular carcinoma (HCC) in cirrhosis. However, the strict assessment of hepatic parenchymal areas uninvolved with HCC has not been investigated. Aim To determine if liver stiffness of nonmalignant hepatic parenchyma using magnetic resonance elastography (MRE) is higher in patients with HCC compared with controls. Methods Cases were defined by compensated cirrhosis with a Child-Turcotte-Pugh score <7 and HCC by radiological criteria or histology. Control subjects with compensated cirrhosis were frequency matched with cases by gender and disease aetiology. Overt manifestations of portal hypertension and previous therapy for liver disease or HCC were exclusion criteria. Region of interest analyses were performed on hepatic parenchyma regions distant to HCC location among cases. Results Thirty patients with HCC and 60 matched controls comprised the study cohort. The mean age for cases was 64 +/- 10 years (range, 45-85) with 70% being men. Major disease aetiologies were chronic viral hepatitis (57%), non-alcoholic fatty liver disease (33%) and alcohol (10%). Twenty-eight (93%) patients had solitary HCC lesions with a mean size of 5.2 cm (range, 2-14 cm). However, patients with HCC had similar liver stiffness among uninvolved areas distant to HCC lesions, when compared with controls without HCC (mean, 6.1 +/- 2.0 vs. 6.3 +/- 2.5 kPa, P = 0.7). Conclusion In contrast to previous studies with transient elastography, we did not observe a systematic association between liver stiffness assessed using MRE and the presence of HCC in patients with compensated cirrhosis. Aliment Pharmacol Ther 2011;34: 83-91

关键词： Portal Hypertension AVERAGE PARTICLE SIZE human-centered computing Magnetic Resonance Elastography liver stiffness

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Value of hepatic venous pressure gradient measurement before liver resection for hepatocellular carcinoma

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BRITISH JOURNAL OF SURGERY 2011年第12期98卷 1752-1758页

作者： Stremitzer, S. Tamandl, D. Kaczirek, K. Maresch, J. Abbasov, B. Payer, B. A. Ferlitsch, A. Gruenberger, T. Med Univ Vienna Dept Gen Surg Hepatobiliary Serv A-1090 Vienna Austria Med Univ Vienna Clin Inst Pathol A-1090 Vienna Austria Med Univ Vienna Dept Gastroenterol & Hepatol A-1090 Vienna Austria

Background: Portal hypertension associated with liver cirrhosis increases the risk of postoperative complications after liver resection for hepatocellular carcinoma (HCC). This study assessed the role of preoperative hepatic venous pressure gradient (HVPG) assessment in identifying portal hypertension. Methods: All patients who underwent liver resection for HCC between January 2000 and December 2009 at the Department of General Surgery, Medical University Vienna, were analysed retrospectively. HVPG was assessed prospectively in a subset of patients before liver resection. The influence of this assessment on postoperative complications was investigated. Results: A total of 132 patients were enrolled, of whom 39 underwent HVPG measurement. Mean(s.d.) HVPG was 6.4(3.0) and 4.3(1.4) mmHg in patients with and without postoperative complications respectively (P = 0.028). Complication rates differed significantly at a cut-off HVPG value of 5 mmHg: 11 of 21 patients with a gradient of 1-5 mmHg developed complications versus 12 of 14 patients with a higher value (P = 0.045). HVPG exceeding 5 mmHg was associated with worse liver fibrosis (P = 0.004), higher rates of postoperative liver dysfunction (5 of 13 versus 1 of 18;P = 0.022) and ascites (7 of 14 versus 3 of 21;P = 0.022), and a longer hospital stay (median (range) 11 (7-26) versus 8 (4-20) days;P = 0.034). Overall postoperative morbidity did not differ between patients who had preoperative HVPG assessment and those who did not (P = 0.142). Conclusion: Preoperative HVPG assessment predicted liver fibrosis and postoperative complications.

关键词： mmHg Liver Fibrosis Liver Dysfunction Postoperative Complications Patients Hepatocellular Cancer Hepatectomy Portal Hypertension Venous Pressure human-centered computing

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What Is the Best Staging System for Hepatocellular Carcinoma in the Setting of Liver Transplantation?

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LIVER TRANSPLANTATION 2011年第S2期17卷 S26-S33页

作者： Olthoff, Kim M. Forner, Alejandro Huebscher, Stefan Fung, John Univ Penn Dept Surg Div Transplantat Philadelphia PA 19104 USA Univ Barcelona Barcelona Clin Liver Canc Grp Hosp Clin Barcelona August Pi I Sunyer Inst Biomed ResLiver Unit Barcelona Spain Network Ctr Biomed Res Hepat & Digest Dis Barcelona Spain Univ Birmingham Sch Canc Sci Birmingham W Midlands England Queen Elizabeth Hosp Dept Cellular Pathol Birmingham B15 2TH W Midlands England Transplant Ctr Dept Gen Surg Inst Digest Dis Cleveland OH USA

To assess the prognosis of all HCC patients, the beststaging system should take into account tumor stage,liver function, and physical status. In addition, theprognosis should be modified according to the *** is no worldwide consensus about the useof any HCC staging system for all HCC patients, andthe systems vary significantly by country. The TNMand Okuda staging systems are most commonly usedinternationally. The BCLC and CLIP staging systemsare used most frequently in Europe, whereas the JISsystem has been accepted as a standard in *** BCLC staging system is the only system thatlinks the prognosis with treatment recommendations,and it has been used in several major trials of HCCtherapy to define the patient population to berecruited and to stratify the patients into separateprognostic categories. It has been validated in severallarge patient populations around the world and hasbeen endorsed by several societies as a guide for clinicaldecision making. The sixth edition of the TNM systemis most widely used for determining a patient\'s prognosis after surgery or transplantation, and it hashigh predictive value after transplantation and *** has been validated in numerous patient populationsand forms the basis for many other stagingsystems and allocation policies. Unfortunately, thepathological TNM stage is not known before transplantation,and it plays an important role in determining posttransplant survival.

关键词： Patients Staging Hepatocellular Cancer human-centered computing Prognosis Transplantation patient history of liver transplantation Liver Transplantation

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The Role of MicroRNAs in human Liver Cancers

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SEMINARS IN ONCOLOGY 2011年第6期38卷 752-763页

作者： Braconi, Chiara Henry, Jon C. Kogure, Takayuki Schmittgen, Thomas Patel, Tushar Mayo Clin Jacksonville FL 32224 USA Ohio State Univ Columbus OH 43210 USA

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver of global importance. Recent studies of the expression and role of microRNA (miRNA) in HCC are providing new insights into disease pathogenesis. In addition, therapeutic efforts targeting specific miRNAs are being evaluated in animal models of HCC. The potential of miRNAs as biomarkers of disease or prognostic markers is being explored. Herein, we review studies of miRNA expression in human HCC, and discuss recent advances in knowledge about the involvement and role of selected miRNAs in disease pathogenesis, as biomarkers, or as therapeutic targets for HCC.

关键词： MicroRNAs Cancer of Liver Biological Markers human-centered computing

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Evaluation of ERCC1 Expression for Cisplatin Sensitivity in human Hepatocellular Carcinoma

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ANNALS OF SURGICAL ONCOLOGY 2011年第4期18卷 1204-1211页

作者： Ueda, Shigeru Shirabe, Ken Morita, Kazutoyo Umeda, Kenji Kayashima, Hiroto Uchiyama, Hideaki Soejima, Yuji Taketomi, Akinobu Maehara, Yoshihiko Kyushu Univ Grad Sch Med Sci Dept Surg & Sci Fukuoka Japan

Excision repair cross-complementation group 1 (ERCC1) is one of the key enzymes in DNA repair. This study was designed to investigate the correlation between ERCC1 expression and chemosensitivity to cisplatin (CDDP) in patients with hepatocellular carcinoma (HCC). Eighty-seven HCC samples were analyzed by immunohistochemistry for ERCC1 and chemosensitivity was assessed by the succinate dehydrogenase inhibition (SDI) test for four anti-cancer agents, including CDDP. The ERCC1 expression was examined in HCC cell lines. ERCC1 siRNA was transfected to PLC/RPF/5 to investigate the correlation of ERCC1 expression and CDDP sensitivity. ERCC1 expression was observed in 33% of nuclei in immunohistochemical examination. Patients were divided into two groups as follows: ERCC1 high expression group (n = 43): more than 33% of the nuclei were stained;ERCC1 low expression group (n = 44): 33% or fewer of the nuclei were stained. Tumor size of low expression group was larger than that in the high expression group (p = 0.02). The succinic dehydrogenase (SD) activity only for CDDP was significantly higher in the high expression group than that in the low expression group (p = 0.02). An increased expression of ERCC1 was shown by immunohistochemical and Western blot analyses in PLC/RPF/5. ERCC1 expression was inhibited by ERCC1 siRNA transfection and the LC50 value (nM) of CDDP was reduced from 25.7 to 12.5 (p = 0.01). Increased ERCC1 expression is associated with CDDP resistance in HCC specimens and cell lines. Therefore, immunohistochemical analysis for resected HCC tissues may be a useful predictor for the effectiveness of adjuvant chemotherapy, using CDDP.

关键词： Hepatocellular Cancer Adjuvant Chemotherapy Cisplatin Chemosensitivity human-centered computing

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Clinicopathological Risk Factors for Recurrence within One Year after Initial Hepatectomy for Hepatocellular Carcinoma

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AMERICAN SURGEON 2011年第5期77卷 572-578页

作者： Hayashi, Michihiro Shimizu, Tetsunosuke Hirokawa, Fumitoshi Inoue, Yoshihiro Komeda, Koji Asakuma, Mitsuhiro Miyamoto, Yoshiharu Takeshita, Atsushi Shibayama, Yuro Tanigawa, Nobuhiko Osaka Med Coll Hosp Dept Gen & Gastroenterol Surg Osaka Japan Osaka Med Coll Hosp Dept Pathol Osaka Japan

Hepatocellular carcinoma (HCC) shows a high rate of recurrence after hepatectomy;predictive factors for early recurrence would help determine optimal therapeutic and management strategies. Among 163 patients with HCC undergoing hepatectomy with curative intent, 46 patients developed recurrence within 1 year. Clinicopathological data were retrospectively analyzed to identify predictive parameters for early recurrence. Survival rates in cases of recurrence within 1 year were worse than those of no recurrence within 1 year or recurrence after 1 year. Protein induced by vitamin K absence/antagonist II (PIVKA-II) greater than 150, positive fucosylated alpha-fetoprotein (L3-AFP), and deviancy from Milan criteria (MC) on preoperative imaging were associated with high risk of early recurrence and total number of these three risk factors predicted the survival. With multivariate analysis, 1) preoperatively, positive factors of two or more among three items of PIVKA-II, L3-AFP, and deviancy from MC;2) and postoperatively, pathological cancer spread (microscopic vascular invasion and/or intrahepatic metastasis) both represented risks for early recurrence. A combination of three preoperative factors, PIVKA-II, L3-AFP, and MC status, in conjunction with the postoperative factor of cancer spread status represents a significant indicator for recurrence within 1 year. Improving the prognosis of patients with HCC would depend on how to adequately treat those at high risk of early recurrence.

关键词： Hepatocellular Cancer Risk Factors Hepatectomy Neoplasm Metastasis Deviant behavior human-centered computing Relapse acarboxy prothrombin

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Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers

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NATURE GENETICS 2011年第8期43卷 797-U108页

作者： Miki, Daiki Ochi, Hidenori Hayes, C. Nelson Abe, Hiromi Yoshima, Tadahiko Aikata, Hiroshi Ikeda, Kenji Kumada, Hiromitsu Toyota, Joji Morizono, Takashi Tsunoda, Tatsuhiko Kubo, Michiaki Nakamura, Yusuke Kamatani, Naoyuki Chayama, Kazuaki RIKEN Lab Digest Dis Ctr Genom Med Hiroshima Japan Hiroshima Univ Grad Sch Biomed Sci Dept Med & Mol Sci Div Frontier Med SciPrograms Biomed Res Hiroshima Japan Dainippon Sumitomo Pharma Co Ltd Pharmacol Res Labs Osaka Japan Toranomon Gen Hosp Dept Hepatol Tokyo Japan Sapporo Kosei Gen Hosp Dept Gastroenterol Sapporo Hokkaido Japan RIKEN Ctr Genom Med Lab Med Informat Yokohama Kanagawa Japan RIKEN Ctr Genom Med Lab Genotyping Dev Yokohama Kanagawa Japan Univ Tokyo Inst Med Sci Mol Med Lab Ctr Human Genome Tokyo Japan RIKEN Ctr Genom Med Stat Lab Yokohama Kanagawa Japan

Chronic viral hepatitis is the most important risk factor for progression to hepatocellular carcinoma (HCC). To identify genetic risk factors for progression to HCC in individuals with chronic hepatitis C virus (HCV), we analyzed 467,538 SNPs in 212 Japanese individuals with chronic HCV with HCC and 765 individuals with chronic HCV without HCC. We identified one intronic SNP in the DEPDC5 locus on chromosome 22 associated with HCC risk and confirmed the association using an independent case-control population (710 cases and 1,625 controls). The association was highly significant when we analyzed the stages separately as well as together (rs1012068, Pcombined = 1.27 x 10(-13), odds ratio = 1.75). The significance level of the association further increased after adjustment for gender, age and platelet count (P = 1.35 x 10(-14), odds ratio = 1.96). Our findings suggest that common variants within the DEPDC5 locus affect susceptibility to HCC in Japanese individuals with chronic HCV infection.

关键词： Hepatocellular Cancer progressions Chronic Hepatitis C Risk Factors Significance level Odds Ratio DEPDC5 gene human-centered computing

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