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Song M, Tao Y, Zhang H, Du M, Guo L, Hu C, Zhang W. Gd-EOB-DTPA-enhanced MR imaging features of hepatocellular carcinoma in non-cirrhotic liver. Magn Reson Imaging 2024; 114:110241. [PMID: 39362318 DOI: 10.1016/j.mri.2024.110241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 09/17/2024] [Accepted: 09/29/2024] [Indexed: 10/05/2024]
Abstract
OBJECTIVE To evaluate clinical, pathological and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) findings of hepatocellular carcinoma (HCC) in non-cirrhotic livers and compare with HCC in cirrhotic livers. METHODS This retrospective study included patients with pathologically confirmed HCC who underwent preoperative Gd-EOB-DTPA-enhanced MRI between January 2015 and October 2021. Propensity scores were utilized to match non-cirrhotic HCCs (NCHCCs) patients with cirrhotic HCCs (CHCCs) patients. The clinical, pathological and MR imaging features of NCHCCs were compared with CHCCs. Correlation between these features and the presence of NCHCCs were analyzed by logistic regression analysis. The predictive efficacy was evaluated using receiver operating characteristic (ROC) analysis. The area under the receiver operating characteristic curve (AUC) was used to compare performance, and the Delong test was used to compare AUCs. RESULTS After propensity score matching (1:3), a total of 144 patients with HCCs (36 NCHCCs and 108 CHCCs) were included. NCHCCs were larger in tumor size than CHCCs (P < 0.001, Cohen's d = 0.737). NCHCCs were more common in patients who have hepatitis C (5.6 % vs 1.9 %, P > 0.05) or have no known liver disease (11.1 % vs 0.9 %, P = 0.004), while hepatitis B was more common in CHCC patients (83.3 % vs 97.2 %, P = 0.003). Compared with CHCCs, NCHCCs more frequently demonstrated non-smooth tumor margin (P = 0.001, Cramer's V = 0.273), peri-tumoral hyperintensity (P < 0.05, Cramer's V = 0.185), hyperintense and heterogeneous signals in hepatobiliary phase (HBP) (P < 0.05). CHCCs were more likely to have satellite nodules compared to NCHCCs (33.3 % vs 57.4 %, P < 0.05, Cramer's V = 0.209). Based on the univariate and multivariate logistic regression analysis, the tumor size, non-smooth tumor margin, heterogeneous intensity in HBP and satellite nodule were significantly correlated to NCHCCs (P all <0.05). ROC curve analysis demonstrated that tumor size and non-smooth tumor margin were potential imaging predictors for the diagnosis of NCHCC, with AUC values of 0.715 and 0.639, respectively. The combination of the two imaging features for identifying NCHCC achieved an AUC value of 0.761, with a sensitivity of 0.889 and a specificity of 0.630. CONCLUSION NCHCCs were more likely to show larger tumor size, non-smooth tumor margin, peri-tumoral hyperintensity, as well as hyperintense and heterogeneous signals in HBP at Gd-EOB-DTPA-enhanced MR imaging compared with NCHCCs. Tumor size and non-smooth tumor margin in HBP may help to discriminate NCHCCs.
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Affiliation(s)
- Mingyue Song
- Department of Radiology, The Fourth Affiliated Hospital of Soochow University, Suzhou 215028, China; Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Yuhao Tao
- Department of Radiology, The Fourth Affiliated Hospital of Soochow University, Suzhou 215028, China; Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Hanjun Zhang
- Department of Radiology, The Fourth Affiliated Hospital of Soochow University, Suzhou 215028, China; Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Mingzhan Du
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Lingchuan Guo
- Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Chunhong Hu
- Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Weiguo Zhang
- Department of Radiology, The Fourth Affiliated Hospital of Soochow University, Suzhou 215028, China; Department of Radiology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
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Arefnezhad R, Ashna S, Rezaei-Tazangi F, Arfazadeh SM, Seyedsalehie SS, Yeganeafrouz S, Aghaei M, Sanandaji M, Davoodi R, Abadi SRK, Vosough M. Noncoding RNAs and programmed cell death in hepatocellular carcinoma: Significant role of epigenetic modifications in prognosis, chemoresistance, and tumor recurrence rate. Cell Biol Int 2024; 48:556-576. [PMID: 38411312 DOI: 10.1002/cbin.12145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 01/26/2024] [Accepted: 02/09/2024] [Indexed: 02/28/2024]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer with a high death rate in the world. The molecular mechanisms related to the pathogenesis of HCC have not been precisely defined so far. Hence, this review aimed to address the potential cross-talk between noncoding RNAs (ncRNAs) and programmed cell death in HCC. All related papers in the English language up to June 2023 were collected and screened. The searched keywords in scientific databases, including Scopus, PubMed, and Google Scholar, were HCC, ncRNAs, Epigenetic, Programmed cell death, Autophagy, Apoptosis, Ferroptosis, Chemoresistance, Tumor recurrence, Prognosis, and Prediction. According to the reports, ncRNAs, comprising long ncRNAs, microRNAs, circular RNAs, and small nucleolar RNAs can affect cell proliferation, migration, invasion, and metastasis, as well as cell death-related processes, such as autophagy, ferroptosis, necroptosis, and apoptosis in HCC by regulating cancer-associated genes and signaling pathways, for example, phosphoinositide 3-kinase/Akt, extracellular signal-regulated kinase/MAPK, and Wnt/β-catenin signaling pathways. It seems that ncRNAs, as epigenetic regulators, can be utilized as biomarkers in diagnosis, prognosis, survival and recurrence rates prediction, chemoresistance, and evaluation of therapeutic response in HCC patients. However, more scientific evidence is suggested to be accomplished to confirm these results.
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Affiliation(s)
- Reza Arefnezhad
- Coenzyme R Research Institute, Tehran, Iran
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Ashna
- Student Research Committee, Islamic Azad University Science and Research Branch, Tehran, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | | | - Seyede Shabnam Seyedsalehie
- Department of Pediatrics, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Ahvaz, Iran
| | - Shaghayegh Yeganeafrouz
- Department of Medical Science, Faculty of Medicine, Islamic Azad University, Medical branch, Tehran, Iran
| | - Melika Aghaei
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mandana Sanandaji
- Department of Physical Education and Sport Sciences, Tehran University, Tehran, Iran
| | | | | | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Institution for Laboratory Medicine, Karolinska Institutet, Experimental Cancer Medicine, Huddinge, Sweden
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Effect of Sirtuin-1 and Wnt/β-Catenin Signaling Pathway in Rat Model of Spinal Cord Injury. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:1799607. [PMID: 35387224 PMCID: PMC8977327 DOI: 10.1155/2022/1799607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 02/25/2022] [Accepted: 02/28/2022] [Indexed: 11/18/2022]
Abstract
Sirtuin-1 (SIRT1) has anti-inflammatory and antioxidant effects and has been reported to be involved in spinal cord injury (SCI). Wnt/β-catenin signal has been shown to play a critical role in the pathogenesis of chronic diseases, and it participated in the recovery of nerve function after SCI. However, the specific link between them in SCI is unclear. In addition, targeting posttraumatic astrocyte apoptosis is crucial for improving neural degeneration and locomotor function. Therefore, in this article, we studied the relationship of β-catenin and SIRT1 using in the SCI rat model and primary astrocyte treated with hydrogen peroxide (H2O2) or lithium chloride (LiCl). Results showed that after SCI, SCI area and motor function recover over time, and β-catenin is gradually increased to the seventh day and then in turn decreases until 4 weeks, positively correlated with cell apoptosis. The expression of SIRT1 and downstream FOXO4 gradually increased, and β-catenin is negatively correlated with SIRT1 expression. Moreover, treatment with H2O2 in primary cultured astrocyte significantly increased β-catenin and Caspase-3 expression, while decreased SIRT1 and Forkhead box O- (FOXO-) 4. The immunofluorescence results are consistent with this. Administration of LiCl further aggravates the above results. These findings suggest that SIRT1 is negatively correlated with β-catenin in SCI, which promotes the apoptosis of motor neuron cells, which may be related to the participation of FOXO4.
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Hu J, Zhang ZQ, Zhu W, Wu ZR, You Y, Liu Y, Su DW, Wang YB, Gong JP. Comparison of clinicopathological traits and prognostic factors of hepatocellular carcinoma with and without cirrhotic background. Carcinogenesis 2021; 41:1576-1582. [PMID: 32188964 DOI: 10.1093/carcin/bgaa024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 02/21/2020] [Accepted: 03/16/2020] [Indexed: 02/05/2023] Open
Abstract
The difference of the patients bearing hepatocellular carcinoma (HCC) with and without cirrhosis at clinical level has not been completely determined. This study compared their differences in clinicopathological traits and prognostic factors for relapse-free survival (RFS) and overall survival (OS). Animal model was established to validate the result of clinical observation. As a result, 82 patients bearing HCC with no cirrhosis (HCC-NC) and 146 patients bearing HCC with cirrhosis (HCC-C) were included. HCC-NC exhibited shorter prothrombin time and higher plasma albumin than HCC-C. In HCC-NC, satellite nodule was an independent risk factor for OS, and high γ-glutamyl transpeptidase was an independent risk factor for RFS. In HCC-C, female sex was an independent risk factor for OS. Stratified analysis showed the OS and RFS of HCC-NC were better than HCC-C in conditions like without cancer embolus (in the portal vein or bile duct), without lymphadenopathy in hepatic portal, without satellite nodule and with small or high-differentiated tumor. Animal model analysis showed HCC-NC had a higher liver/body weight ratio, less tumor count and smaller max tumor volume than HCC-C. In conclusion, clinicopathological traits and risk factors influencing postoperative OS and RFS differed between patients with HCC-C and HCC-NC.
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Affiliation(s)
- Jian Hu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhi-Qing Zhang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wei Zhu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhen-Ru Wu
- Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yu You
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Liu
- Department of Gastroenterology, The Fifth People's Hospital of Chengdu, Chengdu, Sichuan Province, China
| | - Dai-Wen Su
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yun-Bing Wang
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jian-Ping Gong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Impact of diseased liver parenchyma on perioperative outcome among patients with hepatocellular carcinoma undergoing hepatectomy: Experience from a developing country. Surg Oncol 2020; 35:236-242. [PMID: 32932220 DOI: 10.1016/j.suronc.2020.09.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 05/25/2020] [Accepted: 09/07/2020] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Limited data can be found about surgical outcome of patients with hepatocellular carcinoma (HCC) arising in non-diseased liver. The study aim was to compare short- and long-term outcomes among HCC patients with normal and diseased liver parenchyma, undergoing potentially curative liver resection in a developing country. MATERIALS AND METHODS From November 2001 until January 2017, 228 patients with HCC underwent curative-intent hepatectomy at the University Clinic for Digestive Surgery. From that number, 190 patients were eligible for analysis. Diseased liver (DL) was present in 112 patients while 78 patients had HCC in non-diseased liver (NDL). RESULTS Median age, sex, ASA score, the presence of extrahepatic disease and lobar distribution of tumors were similar in both groups. The number of tumors was higher in DL group, while tumor diameter was higher in NDL group. Anatomic liver resection and major liver resections were performed more commonly in NDL than in DL group (66.7 vs 47.4%, p = 0.008; 33.3 vs. 15.2%, p = 0.003). Postoperative morbidity was significantly higher in DL group (p = 0.004). Overall survival was statistically longer in NDL group (p = 0.024). By univariate analysis potential prognostic factors for long-term survival were identified: presence of chronic HCV infection, presence of cirrhosis, Child-Pugh score B and operative time longer than 240 min. The last two were confirmed by multivariate analysis as independent negative prognostic factors for overall survival. CONCLUSION Liver resection in patients with HCC arising in non-diseased livers, despite of need for extended hepatectomies, provides favorable long-term prognosis.
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Lipid Metabolism in Development and Progression of Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12061419. [PMID: 32486341 PMCID: PMC7352397 DOI: 10.3390/cancers12061419] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/19/2020] [Accepted: 05/27/2020] [Indexed: 12/11/2022] Open
Abstract
: Metabolic reprogramming is critically involved in the development and progression of cancer. In particular, lipid metabolism has been investigated as a source of energy, micro-environmental adaptation, and cell signalling in neoplastic cells. However, the specific role of lipid metabolism dysregulation in hepatocellular carcinoma (HCC) has not been widely described yet. Alterations in fatty acid synthesis, β-oxidation, and cellular lipidic composition contribute to initiation and progression of HCC. The aim of this review is to elucidate the mechanisms by which lipid metabolism is involved in hepatocarcinogenesis and tumour adaptation to different conditions, focusing on the transcriptional aberrations with new insights in lipidomics and lipid zonation. This will help detect new putative therapeutic approaches in the second most frequent cause of cancer-related death.
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Abstract
Development of hepatocellular carcinoma (HCC) is usually preceded by chronic liver injury and ongoing liver diseases. Liver cirrhosis reflects the outcome of long-term liver injury and is associated with an increased risk of developing HCC. However, HCC also arises in individuals without cirrhosis and bears several characteristics distinct from HCC in the cirrhotic liver. The molecular characteristics, prognosis, and surveillance of noncirrhotic HCC have not been adequately studied. In this review, we update readers and researchers in the field with the latest understanding of the epidemiology, etiology, clinical features, diagnosis, treatment strategies, prognosis, and surveillance of noncirrhotic HCC.
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Yao J, Zhang X, Li J, Zhao D, Gao B, Zhou H, Gao S, Zhang L. Silencing TRIP13 inhibits cell growth and metastasis of hepatocellular carcinoma by activating of TGF-β1/smad3. Cancer Cell Int 2018; 18:208. [PMID: 30564064 PMCID: PMC6296061 DOI: 10.1186/s12935-018-0704-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 12/11/2018] [Indexed: 02/07/2023] Open
Abstract
Background TRIP13 is highly expressed in several cancers and is closely connected with cancer progression. However, its roles on the growth and metastasis of hepatocellular carcinoma (HCC), and the underlying mechanism are still unclear. Methods Combining bioinformatics with previous studies, the correlation between TRIP13 and HCC was predicted. TRIP13 expressions from 52 HCC patients and several cell lines were determined. The effects of silencing TRIP13 on cell viability, apoptosis, migration and invasion were respectively detected using CCK-8, flow cytometry and Transwell. qRT-PCR and western blot were performed to reveal associated mechanism. A HCC model was established in BALB/c-nu mice by transplanting HepG2 cells. TRIP13 protein expression and apoptosis in mice tissues were accordingly detected by Immunohistochemistry and TUNEL. Results High expression of TRIP13 in HCC affected the survival rate and it was enriched in RNA degradation and fatty acid metabolism according to bioinformatics and prediction from previous literature. Increased expression of TRIP13 in HCC patient tissues was associated with the progression of HCC. Silencing TRIP13 inhibited cell viability, migration and invasion, and induced cell apoptosis. TRIP13 knockdown also suppressed the formation of tumor in vivo. Meanwhile, silencing TRIP13 decreased the expressions of Ki67 and MMP-2 and increased the expressions of TIMP-2, active-caspase-3 and TGF-β1/smad3 signaling- related genes. Conclusions Silencing TRIP13 acts as a tumor suppresser of HCC to repress cell growth and metastasis in vitro and in vivo, and such a phenomenon possibly involved activation of TGF-β1/smad3 signaling.
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Affiliation(s)
- Jianning Yao
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Xuexiu Zhang
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Jiaheng Li
- 2Reproductive Medicine Department, The Third Affiliated Hospital of Zhengzhou University, No.7 Kangfuqian Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Dongyao Zhao
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Bing Gao
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Haining Zhou
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Shilin Gao
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Lianfeng Zhang
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
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Liver clear cell foci and viral infection are associated with non-cirrhotic, non-fibrolamellar hepatocellular carcinoma in young patients from South America. Sci Rep 2018; 8:9945. [PMID: 30061721 PMCID: PMC6065419 DOI: 10.1038/s41598-018-28286-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 06/19/2018] [Indexed: 02/07/2023] Open
Abstract
We previously described a divergent clinical and molecular presentation of hepatocellular carcinoma (HCC) in Peru. The present study aimed to further characterize the tissue features associated with this singular nosological form of HCC in order to gain insight into the natural history of the disease. We performed an exploratory analysis of the histology of both tumor and non-tumor liver (NTL) tissues from 50 Peruvian HCC patients, and compared with that of 75 individuals with non-HCC liver tumor or benign liver lesions as a baseline for NTL features. We complemented this approach with a transcriptome analysis in a subset of NTL tissue samples and also performed an ultra-sensitive hepatitis B virus (HBV) detection in liver tissues of the patients. Overall, results highlighted the low rate of liver parenchymal alterations in a young patient cohort (median age: 40 years old), despite a strong prevalence of underlying HBV infection (c. 67%). Withal, liver clear cell foci of cellular alteration were genuinely associated with HCC and appended to some changes in immune and G protein-coupled receptor gene expression ontologies. Our findings confirm the occurrence of a particular setting of HCC in South America, a region where the pathophysiology of liver cancer remains largely unexplored.
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Ng KY, Chan LH, Chai S, Tong M, Guan XY, Lee NP, Yuan Y, Xie D, Lee TK, Dusetti NJ, Carrier A, Ma S. TP53INP1 Downregulation Activates a p73-Dependent DUSP10/ERK Signaling Pathway to Promote Metastasis of Hepatocellular Carcinoma. Cancer Res 2017; 77:4602-4612. [PMID: 28674078 DOI: 10.1158/0008-5472.can-16-3456] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 05/26/2017] [Accepted: 06/27/2017] [Indexed: 11/16/2022]
Abstract
Identifying critical factors involved in the metastatic progression of hepatocellular carcinoma (HCC) may offer important therapeutic opportunities. Here, we report that the proapoptotic stress response factor TP53INP1 is often selectively downregulated in advanced stage IV and metastatic human HCC tumors. Mechanistic investigations revealed that TP53INP1 downregulation in early-stage HCC cells promoted metastasis via DUSP10 phosphatase-mediated activation of the ERK pathway. The DUSP10 promoter included putative binding sites for p73 directly implicated in modulation by TP53INP1. Overall, our findings show how TP53INP1 plays a critical role in limiting the progression of early-stage HCC, with implications for developing new therapeutic strategies to attack metastatic HCC. Cancer Res; 77(17); 4602-12. ©2017 AACR.
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Affiliation(s)
- Kai-Yu Ng
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Lok-Hei Chan
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Stella Chai
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Man Tong
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Xin-Yuan Guan
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong.,State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Nikki P Lee
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Yunfei Yuan
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Dan Xie
- State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Terence K Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
| | - Nelson J Dusetti
- Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France
| | - Alice Carrier
- Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France
| | - Stephanie Ma
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong. .,State Key Laboratory for Liver Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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Cao SW, Huang JL, Chen J, Hu YW, Hu XM, Ren TY, Zheng SH, Lin JD, Tang J, Zheng L, Wang Q. Long non-coding RNA UBE2CP3 promotes tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. Oncotarget 2017; 8:65370-65385. [PMID: 29029437 PMCID: PMC5630337 DOI: 10.18632/oncotarget.18524] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 06/02/2017] [Indexed: 01/17/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly aggressive, solid malignancy that has a poor prognosis. Long non-coding RNAs (lncRNAs) have been found to be dysregulated in various cancers, including HCC. However, the molecular mechanism involving lncRNAs in HCC remains largely unknown. In this study, lncRNAs differentially expressed between HCC and corresponding non-cancerous tissue were identified by microarray analysis. A specific differentially expressed lncRNA UBE2CP3 (ubiquitin conjugating enzyme E2 C pseudogene 3) was identified. LncRNA UBE2CP3 was frequently up-regulated in HCC samples as assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) experiments. Clinical data showed that high levels of lncRNA UBE2CP3 were correlated with poor prognosis in HCC patients. Functional studies demonstrated that over-expression of lncRNA UBE2CP3 promoted cell invasion and migration in vitro and in vivo. Mechanistically, enhanced expression of lncRNA UBE2CP3 increased the expression of Snail1 and N-cadherin, but decreased the expression of E-cadherin, thus promoting the process of epithelial to mesenchymal transition (EMT) and finally inducing cell invasion and migration. Furthermore, serum levels of lncRNA UBE2CP3 were increased in HCC patients and decreased after surgery. Our results suggest that lncRNA UBE2CP3 promotes the metastasis of HCC and that serum lncRNA UBE2CP3 may be a new biomarker for the diagnosis of HCC.
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Affiliation(s)
- Shun-Wang Cao
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jin-Lan Huang
- Department of Clinical Laboratory, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Jing Chen
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yan-Wei Hu
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiu-Mei Hu
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Ting-Yu Ren
- Department of Clinical Laboratory Medicine Center, Shenzhen Hospital of Southern Medical University, Shenzhen, Guangdong, China
| | - Shi-Hao Zheng
- Department of Neurosurgery, Fujian Provincial Hospital, Fuzhou, Fujian, China
| | - Jin-Duan Lin
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jing Tang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Lei Zheng
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qian Wang
- Laboratory Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Soto-Gutierrez A, Gough A, Vernetti LA, Taylor DL, Monga SP. Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems. Exp Biol Med (Maywood) 2017; 242:1605-1616. [PMID: 28467181 DOI: 10.1177/1535370217707731] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The establishment of metabolic zonation within a hepatic lobule ascribes specific functions to hepatocytes based on unique, location-dependent gene expression patterns. Recently, there have been significant developments in the field of metabolic liver zonation. A little over a decade ago, the role of β-catenin signaling was identified as a key regulator of gene expression and function in pericentral hepatocytes. Since then, additional molecules have been identified that regulate the pattern of Wnt/β-catenin signaling within a lobule and determine gene expression and function in other hepatic zones. Currently, the molecular basis of metabolic zonation in the liver appears to be a 'push and pull' between signaling pathways. Such compartmentalization not only provides an efficient assembly line for hepatocyte functions but also can account for restricting the initial hepatic damage and pathology from some hepatotoxic drugs to specific zones, possibly enabling effective regeneration and restitution responses from unaffected cells. Careful analysis and experimentation have also revealed that many pathological conditions in the liver lobule are spatially heterogeneous. We will review current research efforts that have focused on examination of the role and regulation of such mechanisms of hepatocyte adaptation and repair. We will discuss how the pathological organ-specific microenvironment affects cell signaling and metabolic liver zonation, especially in steatosis, viral hepatitis, and hepatocellular carcinoma. We will discuss how the use of new human microphysiological platforms will lead to a better understanding of liver disease progression, diagnosis, and therapies. In conclusion, we aim to provide insights into the role and regulation of metabolic zonation and function using traditional and innovative approaches. Impact statement Liver zonation of oxygen tension along the liver sinusoids has been identified as a critical liver microenvironment that impacts specific liver functions such as intermediary metabolism of amino acids, lipids, and carbohydrates, detoxification of xenobiotics and as sites for initiation of liver diseases. To date, most information on the role of zonation in liver disease including, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC) have been obtained from animal models. It is now possible to complement animal studies with human liver, microphysiology systems (MPS) containing induced pluripotent stem cells engineered to create disease models where it is also possible to control the in vitro liver oxygen microenvironment to define the role of zonation on the mechanism(s) of disease progression. The field now has the tools to investigate human liver disease progression, diagnosis, and therapeutic development.
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Affiliation(s)
| | - Albert Gough
- 2 Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA.,3 Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Lawrence A Vernetti
- 2 Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA.,3 Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - D L Taylor
- 2 Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA.,3 Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA.,4 Cancer Institute, University of Pittsburgh, Pittsburgh PA 15232, USA
| | - Satdarshan P Monga
- 1 Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15260, USA.,5 Department of Medicine, Pittsburgh, University of Pittsburgh, PA 15260, USA
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Hussin F, Eshkoor SA, Rahmat A, Othman F, Akim A, Eshak Z. Strobilanthes crispus Juice Concentrations and Anticancer Effects on DNA Damage, Apoptosis and Gene Expression in Hepatocellular Carcinoma Cells. Asian Pac J Cancer Prev 2015; 16:6047-53. [DOI: 10.7314/apjcp.2015.16.14.6047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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14
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Monga SP. β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis. Gastroenterology 2015; 148:1294-310. [PMID: 25747274 PMCID: PMC4494085 DOI: 10.1053/j.gastro.2015.02.056] [Citation(s) in RCA: 386] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 02/21/2015] [Accepted: 02/23/2015] [Indexed: 12/11/2022]
Abstract
β-catenin (encoded by CTNNB1) is a subunit of the cell surface cadherin protein complex that acts as an intracellular signal transducer in the WNT signaling pathway; alterations in its activity have been associated with the development of hepatocellular carcinoma and other liver diseases. Other than WNT, additional signaling pathways also can converge at β-catenin. β-catenin also interacts with transcription factors such as T-cell factor, forkhead box protein O, and hypoxia inducible factor 1α to regulate the expression of target genes. We discuss the role of β-catenin in metabolic zonation of the adult liver. β-catenin also regulates the expression of genes that control metabolism of glucose, nutrients, and xenobiotics; alterations in its activity may contribute to the pathogenesis of nonalcoholic steatohepatitis. Alterations in β-catenin signaling may lead to activation of hepatic stellate cells, which is required for fibrosis. Many hepatic tumors such as hepatocellular adenomas, hepatocellular cancers, and hepatoblastomas have mutations in CTNNB1 that result in constitutive activation of β-catenin, so this molecule could be a therapeutic target. We discuss how alterations in β-catenin activity contribute to liver disease and how these might be used in diagnosis and prognosis, as well as in the development of therapeutics.
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Affiliation(s)
- Satdarshan Pal Monga
- Department of Pathology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
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15
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Gao S, Wang K. DNA methylation in liver diseases. World J Clin Infect Dis 2014; 4:41-49. [DOI: 10.5495/wjcid.v4.i4.41] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 07/24/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023] Open
Abstract
Recently, growing evidences show that the combination of epigenetic and genetic abnormalities contribute together to the development of liver diseases. DNA methylation is a very important epigenetic mechanism in human beings. It refers to addition of the methyl groups to DNA and mainly occurs at cytosine adjacent to guanine. DNA methylation is prevalent across human genome and is essential for the normal human development, while its dysfunction is associated with many human diseases. A deep understanding of DNA methylation may provide us deep insight into the origination of liver diseases. Also, it may provide us new tools for diseases diagnosis and prognosis prediction. This review summarized recent progress of DNA methylation study and provided an overview of DNA methylation and liver diseases. Meanwhile, the association between DNA methylation and liver diseases including hepatocellular carcinoma, liver fibrosis, nonalcoholic steatohepatitis and liver failure were extensively discussed. Finally, we discussed the potential of DNA methylation therapeutics for liver diseases and the value of DNA methylation as biomarkers for liver diseases diagnosis and prognosis prediction. This review aimed to provide the emerging DNA methylation information about liver diseases. It might provide essential information for managing and care of these patients.
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Arnaoutakis DJ, Mavros MN, Shen F, Alexandrescu S, Firoozmand A, Popescu I, Weiss M, Wolfgang CL, Choti MA, Pawlik TM. Recurrence patterns and prognostic factors in patients with hepatocellular carcinoma in noncirrhotic liver: a multi-institutional analysis. Ann Surg Oncol 2014; 21:147-154. [PMID: 23959056 DOI: 10.1245/s10434-013-3211-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) primarily affects patients with a cirrhotic liver. Reports on the characteristics of patients with HCC in noncirrhotic liver, as well as predictors of recurrence and survival, are scarce. METHODS Between 1992 and 2011, 334 patients treated for HCC in noncirrhotic liver were identified from three major hepatobiliary centers. Clinicopathological characteristics were analyzed and independent predictors of recurrence and overall survival were identified using Cox proportional hazards models. RESULTS Median patient age was 58 years and 77 % were male. Most patients had a solitary (81 %) and poorly or undifferentiated tumor (56 %); median size was 6.5 cm. The majority of patients (96 %) underwent liver resection (microscopically negative margins in 94 %), whereas a few had transarterial chemoembolization or transplantation (4 %). Median recurrence-free survival (RFS) was 2.5 years, and 1- and 5-year RFS was 71.1, and 35 %, respectively. Elevated alkaline phosphatase levels [hazards ratio (HR) = 1.82], poor tumor differentiation (HR = 1.4), macrovascular invasion (HR = 2.18), and the presence of satellite lesions (HR = 1.9), or intrahepatic metastases (HR = 2.59) were independently associated with shorter RFS; in contrast, an intact tumor capsule independently prolonged RFS (HR = 0.46). Median overall survival was 5.9 years, and 1- and 5-year overall survival was 86.9, and 54.5 %, respectively. Tumor size ≥5 cm (HR = 2.27), macrovascular (HR = 2.72) or adjacent organ invasion (HR = 3.34), and satellite lesions (HR = 2.18) were independently associated with shorter overall survival, whereas an intact tumor capsule showed a protective effect (HR = 0.51). CONCLUSIONS Following resection of HCC in the setting of no cirrhosis, more than one-half of patients were alive after 5 years. However, even among patients with no cirrhosis, recurrence was common. Factors associated with RFS and overall survival included tumor characteristics, such as tumor capsule, satellite lesions, and vascular invasion.
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Affiliation(s)
- Dean J Arnaoutakis
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Michael N Mavros
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Feng Shen
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Sorin Alexandrescu
- Institute for Digestive Diseases and Liver Transplantation Fundeni, Bucharest, Romania
| | - Amin Firoozmand
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Irinel Popescu
- Institute for Digestive Diseases and Liver Transplantation Fundeni, Bucharest, Romania
| | - Matthew Weiss
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Christopher L Wolfgang
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Michael A Choti
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
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"P53 codon 72 single base substitution in viral hepatitis C and hepatocarcinoma incidences". Indian J Clin Biochem 2014; 29:3-7. [PMID: 24478542 DOI: 10.1007/s12291-013-0317-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Accepted: 03/19/2013] [Indexed: 01/16/2023]
Abstract
Viral infection with hepatitis C virus (HCV) has a high propensity in becoming chronic and it is the major cause of hepatocellular carcinoma (HCC) worldwide. This review was basically established to illustrate the putative role of the P53 gene Arg72Pro polymorphism on various cancer models and viral infections, focusing on HCV and HCC incidences. Authors studied the 72 G/C single base substitution of P53 gene at codon 72 using various polymorphic techniques. Intriguingly, authors investigated that the P53 codon 72 plays a crucial role as risk factor in several cancer models. Others found that there is no association between codon 72 genotypes and HCV disease severity or liver cancer. Moreover, the lack of a significant relationship between this polymorphism and risk of HCC shows that it does not predispose towards hepatocarcinogenesis and the frequent loss of the proline allele in HCV-associated carcinogenesis of the liver plays some critical role in hepatocarcinogenesis. Amazingly, there is a significant correlation between male homozygotes for P53 72Pro with HCV type 1b infection. However, there was no significant difference between the P53 polymorphism and HCV genotypes 2a and 2b. It was concluded that the P53 gene polymorphism at codon 72 has been investigated as potential risk factor in several cancer models and HCV infections.
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Ashour AE, Abd-Allah AR, Korashy HM, Attia SM, Alzahrani AZ, Saquib Q, Bakheet SA, Abdel-Hamied HE, Jamal S, Rishi AK. Thymoquinone suppression of the human hepatocellular carcinoma cell growth involves inhibition of IL-8 expression, elevated levels of TRAIL receptors, oxidative stress and apoptosis. Mol Cell Biochem 2014; 389:85-98. [PMID: 24399465 DOI: 10.1007/s11010-013-1930-1] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Accepted: 12/18/2013] [Indexed: 11/30/2022]
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common solid tumor worldwide. The chemokine interleukin-8 (IL-8) is overexpressed in HCC and is a potential target for therapy. Although the transcription factor NF-κB regulates IL-8 expression, and while thymoquinone (TQ; the most bioactive constituent of black seed oil) inhibits NF-κB activity, the precise mechanisms by which TQ regulates IL-8 and cancer cell growth remain to be clarified. Here, we report that TQ inhibited growth of HCC cells in a dose- and time-dependent manner, caused G2M cell cycle arrest, and stimulated apoptosis. Apoptosis was substantiated by activation of caspase-3 and -9, as well as cleavage of poly(ADP-ribose)polymerase. TQ treatments inhibited expression of NF-κB and suppressed IL-8 and its receptors. TQ treatments caused increased levels of reactive oxygen species (ROS) and mRNAs of oxidative stress-related genes, NQO1 and HO-1. Pretreatment of HepG2 cells with N-acetylcysteine, a scavenger of ROS, prevented TQ-induced cell death. TQ treatment stimulated mRNA expression of pro-apoptotic Bcl-xS and TRAIL death receptors, and inhibited expression of the anti-apoptotic gene Bcl-2. TQ enhanced TRAIL-induced death of HepG2 cells, in part by up-regulating TRAIL death receptors, inhibiting NF-κB and IL-8 and stimulating apoptosis. Altogether, these findings provide insights into the pleiotropic molecular mechanisms of TQ-dependent suppression of HCC cell growth and underscore potential of this compound as anti-HCC drug.
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Affiliation(s)
- Abdelkader E Ashour
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia,
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Kim JM, Kwon CHD, Joh JW, Park JB, Lee JH, Kim SJ, Paik SW, Park CK, Yoo BC. Differences between hepatocellular carcinoma and hepatitis B virus infection in patients with and without cirrhosis. Ann Surg Oncol 2013; 21:458-65. [PMID: 24132624 DOI: 10.1245/s10434-013-3302-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Indexed: 12/23/2022]
Abstract
BACKGROUND In patients with hepatitis B virus (HBV) infections, differences in hepatocellular carcinoma (HCC) between those with liver cirrhosis and those without cirrhosis have not been elucidated. The aim of this study was to compare clinicopathological characteristics and survival between noncirrhotic and cirrhotic patients and to determine prognostic factors for tumor recurrence after hepatectomy in patients with HBV and HCC. METHODS Between 2005 and 2010, 441 curative hepatectomies for HCC in patients with cirrhosis and 454 for HCC in patients without cirrhosis were performed. RESULTS Cirrhotic patients had lower platelet counts, protein induced by vitamin K antagonist-II (PIVKA-II) levels, and tumor size than noncirrhotic patients. HCC differentiation in noncirrhotic patients was poorer than in cirrhotic patients. The 1-, 2-, and 3-year disease-free survival rates were 72.0, 65.6, and 61.0% in noncirrhotic patients, and 68.6, 56.5, and 51.5% in cirrhotic patients, respectively (P = 0.013). However, the 1-, 2-, and 3-year overall survival rates were 92.4, 85.5, and 81.7% in noncirrhotic patients, and 91.9, 86.1, and 82.4% in cirrhotic patients, respectively (P = 0.683). Risk factors for tumor recurrence in each group varied in multivariate analyses. Increased age, high platelet counts, microvascular invasion, serosal invasion, and intrahepatic metastasis predisposed to tumor recurrence in noncirrhotic patients, but elevated PIVKA-II and alkaline phosphatase levels, low serum albumin levels, portal vein invasion, intrahepatic metastasis, and tumor size were predisposing factors for recurrence in cirrhotic patients. CONCLUSIONS The clinicopathologic characteristics and risk factors for tumor recurrence in cirrhotic and noncirrhotic HCC patients with HBV infection differ.
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Affiliation(s)
- Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Purohit V, Rapaka R, Kwon OS, Song BJ. Roles of alcohol and tobacco exposure in the development of hepatocellular carcinoma. Life Sci 2013; 92:3-9. [PMID: 23123447 PMCID: PMC3822918 DOI: 10.1016/j.lfs.2012.10.009] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Revised: 10/01/2012] [Accepted: 10/10/2012] [Indexed: 12/11/2022]
Abstract
The purpose of this report is to summarize the roles of alcohol and tobacco exposure in the development of hepatocellular carcinoma (HCC). Chronic heavy alcohol exposure is a major risk factor for HCC, which is the most frequent type of liver cancer. Alcohol ingestion may initiate and or promote the development of HCC by: 1) acetaldehyde-DNA adduct formation; 2) cytochrome P4502E1-associated reactive oxygen species (ROS) generation , lipid peroxidation, p53 mutation, and conversion of pro-carcinogens to carcinogens; 3) iron accumulation that leads to ROS generation, lipid peroxidation, p53 mutation, and initiation of inflammatory cascade via nuclear factor-KappaB (NF-kB) activation; 4) glutathione depletion leading to oxidative stress; 5) s-adenosylmethionine (SAM) depletion and associated DNA hypomethylation of oncogenes ; 6) retinoic acid depletion and resultant hepatocyte proliferation via up-regulation of activator protein-1 (AP-1); 7) initiating an inflammatory cascade through increased transfer of endotoxin from intestine to liver, Kupffer cell activation via CD14/toll-like receptor-4 (TLR-4), oxidative stress, NF-kB or early growth response-1(Egr-1) activation, and generation of inflammatory cytokines and chemokines; 8) induction of liver fibrosis; and 9) decreasing the number and/or function of natural killer cells. Tobacco exposure is also a risk factor for HCC. It may contribute to the initiation and promotion of HCC due the presence of mutagenic and carcinogenic compounds as well as by causing oxidative stress due to generation of ROS and depletion of endogenous antioxidants. Simultaneous exposure to alcohol and tobacco is expected to promote the development of HCC in an additive and/or synergistic manner.
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Affiliation(s)
- Vishnudutt Purohit
- Chemistry and Physiological Systems Research Branch, Division of Basic Neuroscience & Behavioral Research, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD 20892, USA.
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Abstract
The purpose of this report is to summarize the roles of alcohol and tobacco exposure in the development of hepatocellular carcinoma (HCC). Chronic heavy alcohol exposure is a major risk factor for HCC, which is the most frequent type of liver cancer. Alcohol ingestion may initiate and or promote the development of HCC by: 1) acetaldehyde-DNA adduct formation; 2) cytochrome P4502E1-associated reactive oxygen species (ROS) generation , lipid peroxidation, p53 mutation, and conversion of pro-carcinogens to carcinogens; 3) iron accumulation that leads to ROS generation, lipid peroxidation, p53 mutation, and initiation of inflammatory cascade via nuclear factor-KappaB (NF-kB) activation; 4) glutathione depletion leading to oxidative stress; 5) s-adenosylmethionine (SAM) depletion and associated DNA hypomethylation of oncogenes ; 6) retinoic acid depletion and resultant hepatocyte proliferation via up-regulation of activator protein-1 (AP-1); 7) initiating an inflammatory cascade through increased transfer of endotoxin from intestine to liver, Kupffer cell activation via CD14/toll-like receptor-4 (TLR-4), oxidative stress, NF-kB or early growth response-1(Egr-1) activation, and generation of inflammatory cytokines and chemokines; 8) induction of liver fibrosis; and 9) decreasing the number and/or function of natural killer cells. Tobacco exposure is also a risk factor for HCC. It may contribute to the initiation and promotion of HCC due the presence of mutagenic and carcinogenic compounds as well as by causing oxidative stress due to generation of ROS and depletion of endogenous antioxidants. Simultaneous exposure to alcohol and tobacco is expected to promote the development of HCC in an additive and/or synergistic manner.
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Li Q, Gao Y, Jia Z, Mishra L, Guo K, Li Z, Le X, Wei D, Huang S, Xie K. Dysregulated Krüppel-like factor 4 and vitamin D receptor signaling contribute to progression of hepatocellular carcinoma. Gastroenterology 2012; 143:799-810.e2. [PMID: 22677193 PMCID: PMC3653768 DOI: 10.1053/j.gastro.2012.05.043] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2011] [Revised: 05/24/2012] [Accepted: 05/26/2012] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Krüppel-like factor 4 (KLF4) is a transcription factor and putative tumor suppressor. However, little is known about its effects in hepatocellular carcinogenesis. We investigated the clinical significance, biologic effects, and mechanisms of dysregulated KLF4 signaling. METHODS We performed microarray analysis of hepatocellular carcinoma (HCC) tissues. We used molecular biology analyses and animal models to evaluate activation and function of KLF4-vitamin D receptor (VDR) pathway. RESULTS Expression of KLF4 protein was decreased or lost in primary HCC samples, in particular, lymph node metastases, compared with normal liver tissues. Loss of KLF4 from primary tumors was significantly associated with reduced survival time and was identified as a prognostic marker. Most human HCC cell lines had losses or substantial decreases in levels of KLF4. Exogenous expression of KLF4 in HCC cells upregulated expression of mesenchymal-epithelial transition (MET) and inhibited their migration, invasion, and proliferation in vitro. When these cells were injected into mice, tumors grew more slowly and metastasis was inhibited, compared with HCC cells that did not express KLF4. VDR is a direct transcriptional target of KLF4; we identified 2 sites in the VDR promoter that bound specifically to KLF4. Increased expression of VDR sensitized tumor cells to the inhibitory effects of vitamin D. CONCLUSIONS KLF4 binds to the promoter of VDR to regulate its expression; levels of KLF4 are reduced and levels of VDR are increased in HCC cell lines and primary tumor samples. Expression of KLF4 in HCC cells sensitizes them to the anti-proliferative effects of VD3. This pathway might be manipulated to prevent or treat liver cancer.
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MESH Headings
- Animals
- Binding Sites
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/secondary
- Cell Movement
- Cell Proliferation
- Disease Progression
- Epithelial-Mesenchymal Transition
- Female
- Gene Expression Profiling/methods
- Gene Expression Regulation, Neoplastic
- Hep G2 Cells
- Humans
- Immunohistochemistry
- Kruppel-Like Factor 4
- Kruppel-Like Transcription Factors/genetics
- Kruppel-Like Transcription Factors/metabolism
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Lymphatic Metastasis
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasm Invasiveness
- Oligonucleotide Array Sequence Analysis
- Prognosis
- Promoter Regions, Genetic
- Receptors, Calcitriol/genetics
- Receptors, Calcitriol/metabolism
- Signal Transduction
- Time Factors
- Tissue Array Analysis/methods
- Transfection
- Tumor Burden
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Affiliation(s)
- Qi Li
- Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China; Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China; Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yong Gao
- Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China; Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
| | - Zhiliang Jia
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lopa Mishra
- Department of Gastroenterology and Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kun Guo
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zhiwei Li
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiangdong Le
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Daoyan Wei
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Suyun Huang
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Keping Xie
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Lee MJ, Xu DY, Li H, Yu GR, Leem SH, Chu IS, Kim IH, Kim DG. Pro-oncogenic potential of NM23-H2 in hepatocellular carcinoma. Exp Mol Med 2012; 44:214-24. [PMID: 22192927 PMCID: PMC3317485 DOI: 10.3858/emm.2012.44.3.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
NM23 is a family of structurally and functionally conserved proteins known as nucleoside diphosphate kinases (NDPK). There is abundant mRNA expression of NM23-H1, NM23-H2, or a read through transcript (NM23-LV) in the primary sites of hepatocellular carcinoma (HCC). Although the NM23-H1 protein is implicated as a metastasis suppressor, the role of NM23-H2 appears to be less understood. Thus, the aim of this study was to examine whether NM23-H2 is associated with hepatocarcinogenesis. The level of NM23-H2 expression in tumor tissues and the surrounding matrix appeared to be independent of etiology and tumor differentiation. Its subcellular localization was confined to mainly the cytoplasm and to a lesser extent in the nucleus. Ectopic expression of NM23-H2 in NIH3T3 fibroblasts and HLK3 hepatocytes showed a transformed morphology, enhanced focus formation, and allowed anchorage-independent growth. Finally, NIH3T3 fibroblasts and HLK3 hepatocytes stably expressing NM23-H2 produced tumors in athymic mice and showed c-Myc over-expression. In addition, NF-κB and cyclin D1 expression were also increased by NM23-H2. Lentiviral delivery of NM23-H2 shRNA inhibited tumor growth of xenotransplanted tumors produced from HLK3 cells stably expressing NM23-H2. Collectively, these results indicate that NM23-H2 may be pro-oncogenic in hepatocarcinogenesis.
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Affiliation(s)
- Mi-Jin Lee
- Division of GI and Hepatology, The Research Institute of Clinical Medicine, Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju 561-712, Korea
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Young AL, Adair R, Prasad KR, Toogood GJ, Lodge JPA. Hepatocellular carcinoma within a noncirrhotic, nonfibrotic, seronegative liver: surgical approaches and outcomes. J Am Coll Surg 2011; 214:174-83. [PMID: 22137823 DOI: 10.1016/j.jamcollsurg.2011.10.005] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Revised: 09/14/2011] [Accepted: 10/10/2011] [Indexed: 12/23/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) most commonly arises in patients with chronic liver disease. Data on outcomes after liver resection in patients with noncirrhotic, nonfibrotic, seronegative, referred to as a "normal" liver are limited. We aimed to investigate differences in prognostic factors and outcomes between patients presenting with HCC arising in "normal" liver (NLHCC) and that arising in "diseased" liver (DLHCC). STUDY DESIGN All patients undergoing resection for HCC between 1994 and 2008 were assessed. Multivariable analysis of clincopathologic data from the NLHCC group was performed by comparing them with data from the group who had surgery for DLHCC during this period. RESULTS During the 15-year study period, 142 patients underwent liver resection for HCC: 81 for NLHCC and 61 for DLHCC. NLHCCs were more often solitary but were larger and required more major resections. There was no significant difference in survival outcomes between patients who had NLHCC or DLHCC, with overall and recurrence-free 5-year survivals of 60% and 51% in NLHCC and 55% and 33% in DLHCC, respectively. In patients with NLHCC, significant factors predicting overall survival were blood transfusion requirement (p = 0.003) and age (p = 0.009), and the only significant factor at predicting recurrence-free survival was presence of multiple tumors (p = 0.025). In contrast, in DLHCC, the only significant prognostic variables were a preoperative tumor biopsy (p = 0.017) or a high neutrophil-to-lymphocyte ratio (p = 0.001), both of which predicted a poorer recurrence-free survival. CONCLUSIONS HCC presenting in patients with a normal background liver parenchyma appears to present a different spectrum of the disease. However, excellent outcomes can be achieved after liver resection, although this often requires the use of advanced techniques due to late presentation.
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Affiliation(s)
- Alastair L Young
- Department of Hepatobiliary and Transplant Surgery, St James's University Hospital, Leeds, United Kingdom
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SHIN EUN, KIM SOOHEE, JEONG HAEYEON, JANG JAJUNE, LEE KYUNGBUN. Nuclear expression of S-phase kinase-associated protein 2 predicts poor prognosis of hepatocellular carcinoma. APMIS 2011; 120:349-57. [DOI: 10.1111/j.1600-0463.2011.02838.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Mutations in TP53 and CTNNB1 in Relation to Hepatitis B and C Infections in Hepatocellular Carcinomas from Thailand. HEPATITIS RESEARCH AND TREATMENT 2011; 2011:697162. [PMID: 21760996 PMCID: PMC3132492 DOI: 10.1155/2011/697162] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2011] [Accepted: 05/04/2011] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) may develop according to two major pathways, one involving HBV infection and TP53 mutation and the other characterized by HCV infection and CTNNB1 mutation. We have investigated HBV/HCV infections and TP53/CTNNB1 mutations in 26 HCC patients from Thailand. HBV DNA (genotype B or C) was detected in 19 (73%) of the cases, including 5 occult infections and 3 coinfections with HCV. TP53 and CTNNB1 mutations were not mutually exclusive, and most of TP53 mutations were R249S, suggesting a significant impact of aflatoxin-induced mutagenesis in HCC development.
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Maass T, Thieringer FR, Mann A, Longerich T, Schirmacher P, Strand D, Hansen T, Galle PR, Teufel A, Kanzler S. Liver specific overexpression of platelet-derived growth factor-B accelerates liver cancer development in chemically induced liver carcinogenesis. Int J Cancer 2011; 128:1259-68. [PMID: 20506153 DOI: 10.1002/ijc.25469] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
A genetic basis of hepatocellular carcinoma (HCC) has been well-established and major signaling pathways, such as p53, Wnt-signaling, transforming growth factor-β (TGF-β) and Ras pathways, have been identified to be essential to HCC development. Lately, the family of platelet-derived growth factors (PDGFs) has shifted to the center of interest. We have reported on spontaneously developing liver fibrosis in PDGF-B transgenic mice. Since HCC rarely occurs in healthy liver, but dramatically increases at the cirrhosis stage of which liver fibrosis is a preliminary stage, we investigated liver cancer development in chemically induced liver carcinogenesis in these mice. HCC induction was performed by treatment of the mice with diethylnitrosamine and phenobarbital. At an age of 6 months, the tumor development of these animals was analyzed. Not only the development of dysplastic lesions in PDGF-B transgenic mice was significantly increased but also their malignant transformation to HCC. Furthermore, we were able to establish a key role of PDGF-B signaling at diverse stages of liver cancer development. Here, we show that development of liver fibrosis is likely through upregulation of TGF-β receptors by PDGF-B. Additionally, overexpression of PDGF-B also leads to an increased expression of β-catenin as well as vascular endothelial growth factor and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), all factors with established roles in carcinogenesis. We were able to extend the understanding of key genetic regulators in HCC development by PDGF-B and decode essential downstream signals.
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Affiliation(s)
- Thorsten Maass
- Department of Medicine I, Johannes Gutenberg-University, Mainz, Germany
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Lin R, Lü G, Wang J, Zhang C, Xie W, Lu X, Mantion G, Martin H, Richert L, Vuitton DA, Wen H. Time course of gene expression profiling in the liver of experimental mice infected with Echinococcus multilocularis. PLoS One 2011; 6:e14557. [PMID: 21283804 PMCID: PMC3023716 DOI: 10.1371/journal.pone.0014557] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2010] [Accepted: 11/26/2010] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Alveolar echinococcosis (AE) is a severe chronic parasitic disease which behaves like a slow-growing liver cancer. Clinical observations suggest that the parasite, Echinococcus multilocularis (E. multilocularis) influences liver homeostasis and hepatic cell metabolism. However, this has never been analyzed during the time course of infection in the common model of secondary echinococcosis in experimental mice. METHODOLOGY/PRINCIPAL FINDINGS Gene expression profiles were assessed using DNA microarray analysis, 1, 2, 3 and 6 months after injection of E. multilocularis metacestode in the liver of susceptible mice. Data were collected at different time points to monitor the dynamic behavior of gene expression. 557 differentially expressed genes were identified at one or more time points, including 351 up-regulated and 228 down-regulated genes. Time-course analysis indicated, at the initial stage of E. multilocularis infection (month 1-2), that most of up-regulated pathways were related to immune processes and cell trafficking such as chemokine-, mitogen-activated protein kinase (MAPK) signaling, and down-regulated pathways were related to xenobiotic metabolism; at the middle stage (month 3), MAPK signaling pathway was maintained and peroxisome proliferator-activated receptor (PPAR) signaling pathway emerged; at the late stage (month 6), most of up-regulated pathways were related to PPAR signaling pathway, complement and coagulation cascades, while down-regulated pathways were related to metabolism of xenobiotics by cytochrome P450. Quantitative RT-PCR analysis of a random selection of 19 genes confirmed the reliability of the microarray data. Immunohistochemistry analysis showed that proliferating cell nuclear antigen (PCNA) was increased in the liver of E. multilocularis infected mice from 2 months to 6 months. CONCLUSIONS E. multilocularis metacestode definitely exerts a deep influence on liver homeostasis, by modifying a number of gene expression and metabolic pathways. It especially promotes hepatic cell proliferation, as evidenced by the increased PCNA constantly found in all the experimental time-points we studied and by an increased gene expression of key metabolic pathways.
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Affiliation(s)
- Renyong Lin
- Xinjiang Key Laboratory of Echinococcosis and Medical Research Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- Laboratoire de Toxicologie Cellulaire, EA 4267, Faculté de Médecine et Pharmacie, University of Franche-Comté, Besançon, France
| | - Guodong Lü
- Xinjiang Key Laboratory of Echinococcosis and Medical Research Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Junhua Wang
- Xinjiang Key Laboratory of Echinococcosis and Medical Research Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Chuanshan Zhang
- Xinjiang Key Laboratory of Echinococcosis and Medical Research Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Wenjuan Xie
- Xinjiang Key Laboratory of Echinococcosis and Medical Research Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xiaomei Lu
- Xinjiang Key Laboratory of Echinococcosis and Medical Research Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Georges Mantion
- Laboratoire de Toxicologie Cellulaire, EA 4267, Faculté de Médecine et Pharmacie, University of Franche-Comté, Besançon, France
- World Health Organization-Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, Department of Digestive Surgery of Jean Minjoz Hospital, University of Franche-Comté and University Hospital, Besançon, France
| | - Hélène Martin
- Laboratoire de Toxicologie Cellulaire, EA 4267, Faculté de Médecine et Pharmacie, University of Franche-Comté, Besançon, France
| | - Lysiane Richert
- Laboratoire de Toxicologie Cellulaire, EA 4267, Faculté de Médecine et Pharmacie, University of Franche-Comté, Besançon, France
| | - Dominique A. Vuitton
- World Health Organization-Collaborating Centre for the Prevention and Treatment of Human Echinococcosis, Department of Digestive Surgery of Jean Minjoz Hospital, University of Franche-Comté and University Hospital, Besançon, France
- * E-mail: (DAV); (HW)
| | - Hao Wen
- Xinjiang Key Laboratory of Echinococcosis and Medical Research Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
- * E-mail: (DAV); (HW)
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Hepatocellular carcinoma in non-cirrhotic liver: a reappraisal. Dig Liver Dis 2010; 42:341-7. [PMID: 19828388 DOI: 10.1016/j.dld.2009.09.002] [Citation(s) in RCA: 135] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2009] [Revised: 09/06/2009] [Accepted: 09/11/2009] [Indexed: 12/11/2022]
Abstract
Although not frequently, hepatocellular carcinoma (HCC) can ensue in a non-cirrhotic liver. As compared to cirrhotic HCC, this kind of tumour has some peculiarities, such as: (a) a lower male preponderance and a bimodal age distribution; (b) a lower prevalence of the three main risk factors (hepatitis B and C virus infections and alcohol abuse), with an increased prevalence of other etiologic factors, such as exposure to genotoxic substances and sex hormones, inherited diseases, genetic mutations; (c) a more advanced tumour stage at the time of diagnosis, as it is usually detected due to the occurrence of cancer-related symptoms, outside any scheduled surveillance program; (d) a much higher amenability to hepatic resection, due to the low risk of liver failure even after extended parenchymal mutilation; (e) overall and disease-free survivals after resection of non-advanced tumours (meeting the Milano criteria) comparable to that obtained with liver transplantation in cirrhotic patients carrying an early tumour; (f) overall survival strictly dependent on tumour burden (and its recurrence) and barely influenced by liver function.
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p53 Promotes proteasome-dependent degradation of oncogenic protein HBx by transcription of MDM2. Mol Biol Rep 2009; 37:2935-40. [PMID: 19842060 DOI: 10.1007/s11033-009-9855-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2009] [Accepted: 09/28/2009] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus X protein (HBx) is closely involved in the development of hepatocellular carcinoma (HCC). Tumor suppressor p53 was reported to induce HBx degradation and repress its oncogenic function recently, but the molecular mechanism is unknown. In this study, we attempted to identify the underlying mechanism. We found that overexpression of p53 protein reduces the level of HBx protein and shortens its half-life, however, in MDM2 knock out cells, p53 has no effects on degradation of HBx, meanwhile, overexpression of MDM2 in absence of p53 can accelerate turnover of HBx protein. These indicate that p53-mediated HBx degradation is MDM2-dependent. MDM2 interacts with HBx in vitro and in vivo but does not promote its ubiquitination. In consistent with the results above, HCC tissue samples with wild-type p53 hardly detect HBx protein, whereas, HBx always accumulate in the tissues with mutant p53. Our data provide a possible mechanism on how p53 regulate HBx stability and also a new clue for the study of p53 mutation and HCC development.
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Abstract
Wnt/β-catenin signaling is known for its role in embryogenesis as well as carcinogenesis. In the liver, it plays many critical roles during hepatic development and regeneration, and its dysregulation is evident in aberrant hepatic growth during various liver tumors. Its chief cellular roles in the liver include regulation of processes of cell proliferation, apoptosis, oxidative stress and differentiation, which in turn contributes to hepatic growth, zonation, xenobiotic metabolism and other metabolic processes inherent to the liver. Most of these functions of the Wnt/β-catenin signaling are dictated through the highly temporal and tissue-specific or non-specific transcriptional targets of the pathway. In addition, some of the critical functions such as cell-cell adhesion and perhaps maintenance of various junctions that are critical from an epithelial cell biology perspective are also a function of β-catenin, which is the central component of the canonical Wnt pathway. Various animal models and clinical studies have demonstrated the spectra of Wnt/β-catenin signaling in liver health and disease. Thus therapeutic modulation of this pathway for improved hepatic health is inevitable in the future. The current review discusses the advances in our understanding of the Wnt/β-catenin signaling in liver physiology and pathology especially in hepatic metabolism and various tumors in adult liver and goes on to extrapolate the pre-clinical significance and possible translational implications of such findings.
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Monga SPS. Role of Wnt/β-catenin signaling in liver metabolism and cancer. Int J Biochem Cell Biol 2009; 43:1021-9. [PMID: 19747566 DOI: 10.1016/j.biocel.2009.09.001] [Citation(s) in RCA: 132] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2009] [Revised: 07/22/2009] [Accepted: 09/02/2009] [Indexed: 01/11/2023]
Abstract
Wnt/β-catenin signaling is known for its role in embryogenesis as well as carcinogenesis. In the liver, it plays many critical roles during hepatic development and regeneration, and its dysregulation is evident in aberrant hepatic growth during various liver tumors. Its chief cellular roles in the liver include regulation of processes of cell proliferation, apoptosis, oxidative stress and differentiation, which in turn contributes to hepatic growth, zonation, xenobiotic metabolism and other metabolic processes inherent to the liver. Most of these functions of the Wnt/β-catenin signaling are dictated through the highly temporal and tissue-specific or non-specific transcriptional targets of the pathway. In addition, some of the critical functions such as cell-cell adhesion and perhaps maintenance of various junctions that are critical from an epithelial cell biology perspective are also a function of β-catenin, which is the central component of the canonical Wnt pathway. Various animal models and clinical studies have demonstrated the spectra of Wnt/β-catenin signaling in liver health and disease. Thus therapeutic modulation of this pathway for improved hepatic health is inevitable in the future. The current review discusses the advances in our understanding of the Wnt/β-catenin signaling in liver physiology and pathology especially in hepatic metabolism and various tumors in adult liver and goes on to extrapolate the pre-clinical significance and possible translational implications of such findings.
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Affiliation(s)
- Satdarshan Pal Singh Monga
- Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15216, United States.
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Joanna F, van Grunsven LA, Mathieu V, Sarah S, Sarah D, Karin V, Tamara V, Vera R. Histone deacetylase inhibition and the regulation of cell growth with particular reference to liver pathobiology. J Cell Mol Med 2009; 13:2990-3005. [PMID: 19583816 PMCID: PMC4516460 DOI: 10.1111/j.1582-4934.2009.00831.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The transcriptional activity of genes largely depends on the accessibility of specific chromatin regions to transcriptional regulators. This process is controlled by diverse post-transcriptional modifications of the histone amino termini of which reversible acetylation plays a vital role. Histone acetyltransferases (HATs) are responsible for the addition of acetyl groups and histone deacetylases (HDACs) catalyse the reverse reaction. In general, though not exclusively, histone acetylation is associated with a positive regulation of transcription, whereas histone deacetylation is correlated with transcriptional silencing. The elucidation of unequivocal links between aberrant action of HDACs and tumorigenesis lies at the base of key scientific importance of these enzymes. In particular, the potential benefit of HDAC inhibition has been confirmed in various tumour cell lines, demonstrating antiproliferative, differentiating and pro-apoptotic effects. Consequently, the dynamic quest for HDAC inhibitors (HDIs) as a new class of anticancer drugs was set off, resulting in a number of compounds that are currently evaluated in clinical trials. Ironically, the knowledge with respect to the expression pattern and function of individual HDAC isoenzymes remains largely elusive. In the present review, we provide an update of the current knowledge on the involvement of HDACs in the regulation of fundamental cellular processes in the liver, being the main site for drug metabolism within the body. Focus lies on the involvement of HDACs in the regulation of growth of normal and transformed hepatocytes and the transdifferentiation process of stellate cells. Furthermore, extrapolation of our present knowledge on HDAC functionality towards innovative treatment of malignant and non-malignant, hyperproliferative and inflammatory disorders is discussed.
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Affiliation(s)
- Fraczek Joanna
- Department of Toxicology, Vrije Universiteit Brussel, Laarbeeklaan, Brussels, Belgium.
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Ding Z, Qian YB, Zhu LX, Xiong QR. Promoter methylation and mRNA expression of DKK-3 and WIF-1 in hepatocellular carcinoma. World J Gastroenterol 2009; 15:2595-601. [PMID: 19496188 PMCID: PMC2691489 DOI: 10.3748/wjg.15.2595] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the promoter methylation status and mRNA expression of DKK-3 and WIF-1 gene in hepatocellular carcinoma (HCC).
METHODS: DKK-3 and WIF-1 acted as Wnt-antagonists and tumor suppressors, but hypermethylation of the gene promoter and low mRNA expression activated Wnt signaling aberrantly and induced the development of HCC. Methylation status of the DKK-3 and WIF-1 gene promoter was investigated using methylation specific polymerase chain reaction (PCR) in tumor and adjacent non-cancerous tissues from 33 HCC patients and 20 normal liver tissues served as control. The expression of DKK-3 and WIF-1 mRNA was also determined by real-time quantitative reverse transcriptase PCR. The relationship between methylation, mRNA expression, and clinical data, as well as methylation and mRNA expression of the two genes were analyzed.
RESULTS: The methylation of DKK-3 and WIF-1 genes in HCC increased significantly compared with adjacent non-cancerous tissues and normal control tissues (χ2 =7.79, P < 0.05; χ2 = 4.89, P < 0.05), and no significant difference in methylation between adjacent non-cancerous tissues and normal control tissues was observed. In HCC tissues, significant differences in the DKK-3 promoter methylation were observed in age and cirrhosis, and significant differences of the WIF-1 promoter methylation were observed in HBsAg and cirrhosis. The average expression of DKK-3 mRNA in HCC and adjacent non-cancerous tissues was increased significantly compared with normal control tissues. The average expression of WIF-1 mRNA showed no significant difference among the three tissues. The mRNA expression of DKK-3 gene in HCC was decreased as the pathological grade increased.
CONCLUSION: The aberrant promoter methylation and decreased expression of DKK-3 and WIF-1 may be an important mechanism in HCC, and may be a far-reaching significance in early diagnosis and therapy of HCC.
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Hanczko R, Fernandez DR, Doherty E, Qian Y, Vas G, Niland B, Telarico T, Garba A, Banerjee S, Middleton FA, Barrett D, Barcza M, Banki K, Landas SK, Perl A. Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine. J Clin Invest 2009; 119:1546-57. [PMID: 19436114 DOI: 10.1172/jci35722] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2008] [Accepted: 03/11/2009] [Indexed: 01/12/2023] Open
Abstract
Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1-/- and Taldo1+/- mice spontaneously developed HCC, and Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1-/- livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress. Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.
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Affiliation(s)
- Robert Hanczko
- Department of Medicine, College of Medicine, State University of New York, Syracuse, New York 13210, USA
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Ngoka LCM. Dramatic down-regulation of oxidoreductases in human hepatocellular carcinoma hepG2 cells: proteomics and gene ontology unveiling new frontiers in cancer enzymology. Proteome Sci 2008; 6:29. [PMID: 18950483 PMCID: PMC2614416 DOI: 10.1186/1477-5956-6-29] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2008] [Accepted: 10/24/2008] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Oxidoreductases are enzymes that catalyze many redox reactions in normal and neoplastic cells. Their actions include catalysis of the transformation of free, neutral oxygen gas into oxygen free radicals, superoxide, hydroperoxide, singlet oxygen and hydrogen peroxide. These activated forms of oxygen contribute to oxidative stress that modifies lipids, proteins, DNA and carbohydrates. On the other hand, oxidoreductases constitute one of the most important free radical scavenger systems typified by catalase, superoxide dismutase and glutathione peroxidase.In this work, proteomics, Gene Ontology mapping and Directed Acyclic Graphs (DAG) are employed to detect and quantify differential oxidoreductase enzyme expressions between HepG2 cells and normal human liver tissues. RESULTS For the set of bioinformatics calculations whose BLAST searches are performed using the BLAST program BLASTP 2.2.13 [Nov-27-2005], DAG of the Gene Ontology's Molecular Function annotations show that oxidoreductase activity parent node of the liver proteome contains 331 annotated protein sequences, 7 child nodes and an annotation score of 188.9, whereas that of HepG2 cells has 188 annotated protein sequences, 3 child nodes and an annotation score of only 91.9. Overwhelming preponderance of oxidoreductases in the liver is additionally supported by the isomerase DAGs: nearly all the reactions described in the normal liver isomerase DAG are oxidoreductase isomerization reactions, whereas only one of the three child nodes in the HepG2 isomerase DAG is oxidoreductase. Upon normalization of the annotation scores to the parent Molecular Function nodes, oxidoreductases are down-regulated in HepG2 cells by 58%.Similarly, for the set of bioinformatics calculations whose BLAST searches are carried out using BLASTP 2.2.15 [Oct-15-2006], oxidoreductases are down-regulated in HepG2 cells by 56%. CONCLUSION Proteomics and Gene Ontology reveal, for the first time, differential enzyme activities between HepG2 cells and normal human liver tissues, which may be a promising new prognostic marker of Hepatocellular carcinoma.Two independent sets of bioinformatics calculations that employ two BLAST program versions, and searched different databases, arrived at essentially the same conclusion: oxidoreductases are down-regulated in HepG2 cells by approximately 57%, when compared to normal human liver tissues. Down-regulation of oxidoreductases in hepatoma is additionally supported by Gene Ontology analysis of isomerises.
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Affiliation(s)
- Lambert C M Ngoka
- Department of Chemistry, Virginia Commonwealth University, Richmond, 23284-2006, USA.
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Abstract
As for many other tumors, development of hepatocellular carcinoma (HCC) must be understood as a multistep process with accumulation of genetic and epigenetic alterations in regulatory genes, leading to activation of oncogenes and inactivation or loss of tumor suppressor genes (TSG). In the last decades, in addition to genetic alterations, epigenetic inactivation of (tumor suppressor) genes by promoter hypermethylation has been recognized as an important and alternative mechanism in tumorigenesis. In HCC, aberrant methylation of promoter sequences occurs not only in advanced tumors, it has been also observed in premalignant conditions just as chronic viral hepatitis B or C and cirrhotic liver. This review discusses the epigenetic alterations in hepatocellular carcinoma focusing DNA methylation.
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Su H, Zhao J, Xiong Y, Xu T, Zhou F, Yuan Y, Zhang Y, Zhuang SM. Large-scale analysis of the genetic and epigenetic alterations in hepatocellular carcinoma from Southeast China. Mutat Res 2008; 641:27-35. [PMID: 18358501 DOI: 10.1016/j.mrfmmm.2008.02.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2007] [Revised: 01/25/2008] [Accepted: 02/07/2008] [Indexed: 12/31/2022]
Abstract
Our knowledge about molecular alterations during hepatocarcinogenesis is still fragmentary, due to lack of comprehensive genetic and epigenetic analyses in the same set of hepatocellular carcinomas (HCCs). In this study, we conducted a large-scale analysis, including mutation screening in 50 genes and methylation assays in three genes in 54 pairs of HCCs and their neighboring non-cancerous tissues. All samples were collected from the residents in Southeast China. We found HBV infection and chronic hepatitis/cirrhosis in 83.3% and 98.1% of the cases, respectively. Mutations were identified in 18 out of 54 (33.3%) samples, with p53 alterations in 14 cases and beta-catenin mutations in four tumors. No mutations were identified in the neighboring tissues. Interestingly, 9 out of 14 (64.3%) tumors carrying p53 mutations displayed substitution of serine by arginine at codon 249, a characteristic change believed to be induced by aflatoxin-B1. Furthermore, p53 mutation was significantly associated with shorter recurrence-free survival (P=0.004). The results also revealed aberrant methylation in two or more genes in as high as 90% of tumors and 40% of adjacent tissues. The frequency of RASSF1A hypermethylation was much higher than that of p16INK4a and HAI2 in both HCC and neighboring tissues, indicating that deregulation of RASSF1A may precede the other two genes. These data suggest that aberrant methylation occurs before mutation and is an early event in the development of this set of HCC. Our findings highlight p53 as a prognostic factor of HCC and RASSF1A as a potential target in preventing malignant transformation of hepatocytes.
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Affiliation(s)
- Hang Su
- Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China
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Kim YD, Park CH, Kim HS, Choi SK, Rew JS, Kim DY, Koh YS, Jeung KW, Lee KH, Lee JS, Juhng SW, Lee JH. Genetic alterations of Wnt signaling pathway-associated genes in hepatocellular carcinoma. J Gastroenterol Hepatol 2008; 23:110-8. [PMID: 18171349 DOI: 10.1111/j.1440-1746.2007.05250.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Recently, abnormal activation of the Wnt pathway has been found to be involved in the carcinogenesis of HCC. However, the relationship between genetic changes in the Wnt pathway-associated genes and its protein expression has not been studied in patients with HCC and cirrhotic nodules. The purpose of this study is to explore the contribution of inappropriate activation of the Wnt pathway in liver carcinogenesis. METHODS Somatic mutation in exons 3-5 of AXIN1 and exon 3 of beta-catenin were analyzed by direct sequencing and expression of axin and beta-catenin proteins by immunohistochemistry in a series of 36 patients with HCC and cirrhosis. RESULTS The AXIN1 and beta-catenin gene mutations were observed in 25% (9/36) and 2.8% (1/36) of HCCs, respectively. All mutations detected in AXIN1 and beta-catenin genes were missense point mutations. Abnormal nuclear expression of beta-catenin was observed in 11 of 36 cases of HCCs (30.6%), but not in cirrhotic nodules. Reduced or absent expression of axin was seen in 24 of 36 HCCs (66.7%). The abnormal expression of beta-catenin and axin proteins was closely correlated with mutations of AXIN1 and beta-catenin (P < 0.0001 and P = 0.008, respectively). CONCLUSIONS These data suggest that mutation of AXIN1 gene is a frequent and late event for HCC associated with cirrhosis, and is correlated significantly with abnormal expression of axin and beta-catenin. Therefore, activation of Wnt signaling through AXIN1 rather than beta-catenin mutation might play an important role in liver carcinogenesis.
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Affiliation(s)
- Young-Dae Kim
- Department of Internal Medicine, College of Medicine, Chosun University, Gwangju, Korea
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40
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Hiatt T, Trotter JF, Kam I. Hepatocellular carcinoma in a noncirrhotic patient with hereditary hemochromatosis. Am J Med Sci 2007; 334:228-30. [PMID: 17873542 DOI: 10.1097/maj.0b013e3181425209] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
We report the case of a 66-year-old man with genetic hemochromatosis who was found to have hepatocellular carcinoma (HCC) in the absence of cirrhosis. This is a rare and life-threatening complication of noncirrhotic hemochromatosis that has been described only 10 times in the English literature. In addition to presenting our case, we also cite some other potential causes of HCC in noncirrhotic patients that should be clinically considered. Although the incidence of HCC in noncirrhotic hemochromatosis patients is not sufficiently high to warrant routine screening, physicians should be aware that this fatal complication may rarely occur.
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Affiliation(s)
- Tadd Hiatt
- Division of Gastroenterology/Hepatology, University of Colorado Health Sciences Center, Denver, Colorado 80045, USA
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41
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Sirach E, Bureau C, Péron JM, Pradayrol L, Vinel JP, Buscail L, Cordelier P. KLF6 transcription factor protects hepatocellular carcinoma-derived cells from apoptosis. Cell Death Differ 2007; 14:1202-10. [PMID: 17347668 DOI: 10.1038/sj.cdd.4402114] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major public health concern because of the absence of early diagnosis and effective treatments. Efficient diagnosis modalities and therapies to treat HCC are needed. Kruppel-like factor (KLF) family members, such as KLF6, are involved in cell proliferation and differentiation. KLF6 is inactivated in solid tumors, which may contribute to pathogenesis. However, KLF6 status in HCC is controversial. Thus, we undertook the characterization of KLF6 expression and function in HCC and HCC-derived cell lines. We found that HCC, HepG2 and HuH7 cells expressed KLF6 messenger ribonucleic acid and protein. Next, using RNA interference, we demonstrated that inhibiting KLF6 expression in vitro strongly impaired cell proliferation-induced G1-phase arrest, inhibited cyclin-dependent kinase 4 and cyclin D1 expression, and subsequent retinoblastoma phosphorylation. Finally, KLF6 silencing caused p53 upregulation and inhibited Bcl-xL expression, to induce cell death by apoptosis. Taken together, these data demonstrated that KLF6 is essential for HCC-derived cells to evade apoptosis.
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Affiliation(s)
- E Sirach
- INSERM U858, I2MR, Toulouse, France
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42
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Zhu J. DNA methylation and hepatocellular carcinoma. ACTA ACUST UNITED AC 2007; 13:265-73. [PMID: 16858536 DOI: 10.1007/s00534-005-1054-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2005] [Accepted: 09/01/2005] [Indexed: 02/07/2023]
Abstract
The epigenetic makeup of organisms forms a link between the genetic information (DNA sequence) and the gene expression (and therefore phenotype). It dictates the memory for the gene expression pattern that, in turn, specifies cell identity. DNA methylation is the most studied epigenetic mechanism, aberration of which prevails in cancer, resulting in an altered pattern of gene expression and, therefore, cancerous features, including genetic abnormalities: mutations and genome instability. Altered methylation in cancer occurs in two directions. A marked reduction in the overall level of DNA methylation has been linked to the activation of transcription/transposition and the overexpression of protooncogenes. In parallel, there is a common occurrence of a hypermethylated status of the promoter cytosine (CpG) island in genes involved in the negative control of cell growth and in the maintenance of genomic stability; therefore causing transcription silencing. It is thus necessary and important to establish a comprehensive profile of DNA methylation changes in the promoter CpG island in many genes, both for better understanding of the underlying mechanisms and for diagnostic purposes in cancer clinics. Hepatocellular carcinoma is one of the most threatening malignancies in East Asia and Africa. In this short review, I briefly outline our current understanding of DNA methylation in cancer in general, emphasizing its recent progress in hepatocellular carcinoma.
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Affiliation(s)
- Jingde Zhu
- Cancer Epigenetics and Gene Therapy Group, The State-Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University, LN 2200/25, Xietu Road, Shanghai, 200032, China
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43
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Tannapfel A. [Methylation and other new concepts for the origin of hepatocellular carcinoma]. DER PATHOLOGE 2006; 27:284-8. [PMID: 16736175 DOI: 10.1007/s00292-006-0837-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Methylation takes place when a methyl group, comprised of a carbon and three hydrogen atoms (CH3), attaches to the individual DNA bases. This modification of the DNA leads to a change in gene expression. Changes in the methylation status of the DNA belong to the most common gene changes leading to malignant tumours. Recent studies have shown that three different mechanisms play a role in the effect of methylation: global hypomethylation, hypermethylation of individual gene segments and the deregulated expression of DNA methyltransferases. Such DNA methylation is also one of the most homogenous and consistent molecular changes in hepatocellular carcinoma (HCC). Moreover, the hypermethylation of specific genes has been shown to precede the development of malignant tumours. Thus, DNA methylation is a possible biomarker for the early discovery of HCC. The reversibility of methylation also offers a possible future treatment option.
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Affiliation(s)
- A Tannapfel
- Institut für Pathologie der Ruhr Universität, Berufsgenossenschaftliche Kliniken Bergmannsheil, Bürkle-de-la-Camp Platz 1, 44789, Bochum.
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44
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Lee HC, Tian B, Sedivy JM, Wands JR, Kim M. Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Gastroenterology 2006; 131:1208-17. [PMID: 17030190 PMCID: PMC2593881 DOI: 10.1053/j.gastro.2006.07.012] [Citation(s) in RCA: 148] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2006] [Accepted: 06/15/2006] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS The Raf kinase inhibitor protein (RKIP) has been identified as a suppressor of the mitogen-activated protein kinase (MAPK) pathway. Loss of RKIP function promotes tumor metastasis in prostate cancer and melanoma. The insulin-like growth factor I (IGF-I)-mediated MAPK cascade is often activated in hepatocellular carcinoma (HCC), but the role of RKIP in the molecular pathogenesis of these tumors is unknown. This study was performed to evaluate the role of RKIP in the development of HCC. METHODS The levels of RKIP expression in HCC tumor and corresponding peritumoral tissues were determined by immunohistochemistry and Western blot analysis. The underlying mechanisms of RKIP were assessed with immunoblot analysis, Raf kinase activity assay, cell proliferation, and migration assays after either overexpression or knockdown of RKIP expression in HCC cell lines. RESULTS RKIP expression is down-regulated in human HCC compared with adjacent peritumoral tissues. Low RKIP levels were correlated with enhanced extracellular signal-regulated-kinase (ERK)/MAPK pathway activation. Reconstitution experiments antagonized IGF-I-mediated MAPK pathway activation, resulting in reduced nuclear accumulation of phospho-ERK. In contrast, knockdown of RKIP expression using small interfering RNA induced activation of the ERK/MAPK pathway. Ectopic expression of RKIP altered HCC cell proliferation and migration. CONCLUSIONS Our findings indicate that down-regulation of RKIP expression is a major factor in activation of the IGF-I/ERK/MAPK pathway during human hepatocarcinogenesis.
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Affiliation(s)
- Han Chu Lee
- Liver Research Center, Rhode Island Hospital and Brown Medical School, Brown University, Providence, RI 02903
| | - Bo Tian
- Liver Research Center, Rhode Island Hospital and Brown Medical School, Brown University, Providence, RI 02903
| | - John M. Sedivy
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02903
| | - Jack R. Wands
- Liver Research Center, Rhode Island Hospital and Brown Medical School, Brown University, Providence, RI 02903
| | - Miran Kim
- Liver Research Center, Rhode Island Hospital and Brown Medical School, Brown University, Providence, RI 02903
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45
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Chang PC, Chi CW, Chau GY, Li FY, Tsai YH, Wu JC, Wu Lee YH. DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control. Oncogene 2005; 25:1991-2003. [PMID: 16301996 DOI: 10.1038/sj.onc.1209239] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide and is highly correlated with hepatitis virus infection. Our previous report shows that a DEAD box RNA helicase, DDX3, is targeted and regulated by hepatitis C virus (HCV) core protein, which implicates the involvement of DDX3 in HCV-related HCC development. In this study, the potential role of DDX3 in hepatocarcinogenesis is investigated by examining its expression in surgically excised human HCC specimens. Here we report the differential deregulation of DDX3 expression in hepatitis virus-associated HCC. A significant downregulation of DDX3 expression is found in HCCs from hepatitis B virus (HBV)-positive patients, but not from HCV-positive ones, compared to the corresponding nontumor tissues. The expression of DDX3 is differentially regulated by the gender and, moreover, there is a tendency that the downregulation of DDX3 expression in HCCs is more frequent in males than in females. Genetic knockdown of DDX3 with small interfering RNAs (siRNA) in a nontransformed mouse fibroblast cell line, NIH-3T3, results in a premature entry to S phase and an enhancement of cell growth. This enhanced cell cycle progression is linked to the upregulation of cyclin D1 and the downregulation of p21(WAF1) in the DDX3 knockdown cells. In addition, constitutive reduction of DDX3 expression increases the resistance of NIH-3T3 cells to serum depletion-induced apoptosis and enhances the ras-induced anchorage-independent growth, indicating the involvement of DDX3 in cell growth control. These findings together with the previous study suggest that the deregulation of DDX3, a DEAD box RNA helicase with cell growth-regulatory functions, is involved in HBV- and HCV-associated pathogenesis.
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Affiliation(s)
- P-C Chang
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China
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46
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Surgical resection has been considered the optimal treatment approach, but only a small proportion of patients are suitable candidates for surgery, and the relapse rate is high. Approaches to prevent recurrence, including chemoembolization before and adjuvant therapy after surgery, have proven to have a limited benefit; liver transplantation is successful in treating limited-stage HCC because only a minority of patients qualify for transplantation. Therefore, new therapeutic strategies are urgently needed. Because in addition to the classical genetic mechanisms of deletion or inactivating point mutations, epigenetic alterations, such as hyperacetylation of the chromatin-associated histones (responsible for gene silencing), are believed to be involved in the development and progression of HCC, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. In particular, pre-clinical results obtained using HA-But, an HDAC inhibitor in which butyric acid residues are esterified to a hyaluronic acid backbone and characterized by a high affinity for the membrane receptor CD44, indicated that this class of compounds may represent a promising approach for hepatocellular carcinoma treatment.
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Affiliation(s)
- Danila Coradini
- UO Tumor Biology and Experimental Therapy, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy.
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47
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Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. Conventional diagnosis and treatment of this malignancy have been dismal and should be complemented by novel tools. The development and progress of HCC are believed to be caused by the accumulation of genetic changes resulting in altered expression of thousands of cancer-related genes, which can be measured by globe genetic analysis. Gene expression profiling of HCC has been employed to elucidate hepatocarcinogenesis and disclose molecular mechanisms underlying complex clinical features. Identifying phenotype-associated genes/profiles has impacts on current diagnosis and management strategy of HCC. In spite of some pitfalls of this technology and challenges in improving the research process, scrutinous validation of profiling data of HCC combined with other approaches will eventually benefit the patients.
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Affiliation(s)
- Lian-Hai Zhang
- Peking University School of Oncology, Beijing Cancer Hospital, Beijing Institute for Cancer Research, Beijing 100034, China
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48
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Pani G, Fusco S, Colavitti R, Borrello S, Maggiano N, Cravero AAM, Farré SM, Galeotti T, Koch OR. Abrogation of hepatocyte apoptosis and early appearance of liver dysplasia in ethanol-fed p53-deficient mice. Biochem Biophys Res Commun 2005; 325:97-100. [PMID: 15522206 DOI: 10.1016/j.bbrc.2004.09.213] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2004] [Indexed: 12/23/2022]
Abstract
Ethanol consumption represents a major risk factor for cancer development, and a significant fraction of hepatocarcinomas arises in alcoholic liver cirrhosis. Increasing evidence indicates that ethanol acts as a tumor promoter on genetically initiated cells, by increasing the intracellular concentration of reactive oxygen species and promoting tissue necrosis/regeneration and cell proliferation. The tumor suppressor p53 restrains the expansion of carcinogen-initiated cells by inducing cell cycle arrest and apoptosis; accordingly, p53-deficient mice develop spontaneous and chemically induced neoplasms at a much higher frequency than normal mice. In normal mice exposed to a subacute (3 weeks) ethanol intoxication, a significant increase in the number of apoptotic hepatocytes was observed in concomitance with the up-regulation of the mitochondrial superoxide scavenger MnSOD, a reliable indicator of oxidative stress. Cell death occurred in the absence of liver inflammation and necrosis. Ethanol-induced hepatocyte apoptosis was completely abrogated in the p53 null background, suggesting that the tumor suppressor is necessary for hepatocyte death by ethanol. Accordingly, p53 -/- MEF were, unlike wild type cells, completely insensitive up to 0.5M ethanol in the culture medium. Strikingly, marked and widespread signs of dysplasia, with nuclear pleomorphisms and initial loss of normal architecture, heralding malignant transformation, were scored in all the mutant mice exposed to ethanol, but not in the control-fed littermates nor in ethanol-fed normal mice. These observations suggest that p53-dependent apoptosis restrains the tumorigenic effect of ethanol on liver cells, in agreement with the frequent loss of p53 function in HCC, and reveal an unexpected carcinogenic potential of alcohol which appears to be independent from the induction of cirrhosis and hepatocyte regeneration.
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Affiliation(s)
- Giovambattista Pani
- Institute of General Pathology, Catholic University Medical School, Rome, Italy.
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49
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Maeta Y, Shiota G, Okano JI, Murawaki Y. Effect of Promoter Methylation of the p16 Gene on Phosphorylation of Retinoblastoma Gene Product and Growth of Hepatocellular Carcinoma Cells. Tumour Biol 2005; 26:300-5. [PMID: 16254459 DOI: 10.1159/000089288] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2005] [Accepted: 05/11/2005] [Indexed: 11/19/2022] Open
Abstract
The biological significance of hypermethylation of p16 gene promoter in human hepatocellular carcinoma (HCC) cells remains to resolved. In order to clarify the significance of methylation of p16 gene promoter, we examined the methylation status of p16 gene in association with phosphorylation of retinoblastoma gene product (pRb) and cell growth in human HCC cell lines. The presence of methylation was examined by methylation-specific PCR. Expression and phosphorylation of p16 and pRb were examined by Western blot analysis. Genetic changes were analyzed by multiplex PCR and DNA sequencing. The effect of demethylation of p16 was assessed by cell growth. p16 gene promoter was methylated in HuH7 and HLF cells. The demethylating agent, 5-aza-2-deoxycytidine (5-Aza-CdR), upregulated p16 mRNA in HuH6 and HuH7 cells. 5-Aza-CdR increased p16 protein expression in HuH6, HuH7, and HLF cells, and it clearly decreased the phosphorylation level of pRb in HuH6, HuH7 and PLC/PRF/5 cells. Treatment with 5-Aza-CdR inhibited the growth of HuH7 cells. Homozygous deletion and significant mutations were absent. Methylation in the p16 promoter region is biologically significant, being associated with phosphorylation of pRb and cell growth in human HCC cells.
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Affiliation(s)
- Yoshiko Maeta
- Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan
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50
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Boomkens SY, Spee B, IJzer J, Kisjes R, Egberink HF, van den Ingh TSGAM, Rothuizen J, Penning LC. The establishment and characterization of the first canine hepatocellular carcinoma cell line, which resembles human oncogenic expression patterns. COMPARATIVE HEPATOLOGY 2004; 3:9. [PMID: 15566568 PMCID: PMC535891 DOI: 10.1186/1476-5926-3-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2004] [Accepted: 11/26/2004] [Indexed: 12/03/2022]
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most worldwide frequent primary carcinomas resulting in the death of many cirrhotic patients. Unfortunately, the molecular mechanisms of this cancer are not well understood; therefore, we need a good model system to study HCC. The dog is recognized as a promising model for human medical research, namely compared with rodents. The objective of this study was to establish and characterize a spontaneous canine tumor cell line as a potential model for studies on HCC. Results Histomorphological, biochemical, molecular biological and quantitative assays were performed to characterize the canine HCC cell line that originated from a dog with a spontaneous liver tumor. Morphological investigations provided strong evidence for the hepatocytic and neoplastic nature of the cell line, while biochemical assays showed that they produced liver-specific enzymes. PCR analysis confirmed expression of ceruloplasmin, alpha-fetoprotein and serum albumin. Quantitative RT-PCR showed that the canine HCC cell line resembles human HCC based on the measurements of expression profiles of genes involved in cell proliferation and apoptosis. Conclusions We have developed a novel, spontaneous tumor liver cell line of canine origin that has many characteristics of human HCC. Therefore, the canine HCC cell line might be an excellent model for comparative studies on the molecular pathogenesis of HCC.
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Affiliation(s)
- Sacha Y Boomkens
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 8, P.O. Box 80154, 3508 TD Utrecht, The Netherlands
| | - Bart Spee
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 8, P.O. Box 80154, 3508 TD Utrecht, The Netherlands
| | - Jooske IJzer
- Department of Pathobiology, Division of Pathology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands
| | - Ronald Kisjes
- Department of Pathobiology, Division of Pathology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands
| | - Herman F Egberink
- Department of Infectious Diseases and Immunology, Division of Virology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands
| | - Ted SGAM van den Ingh
- Department of Pathobiology, Division of Pathology, Faculty of Veterinary Medicine, Utrecht University, The Netherlands
| | - Jan Rothuizen
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 8, P.O. Box 80154, 3508 TD Utrecht, The Netherlands
| | - Louis C Penning
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 8, P.O. Box 80154, 3508 TD Utrecht, The Netherlands
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