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Liu G, Yang ZF, Sun J, Sun BY, Zhou PY, Zhou C, Guan RY, Wang ZT, Yi Y, Qiu SJ. The LINC00152/miR-205-5p/CXCL11 axis in hepatocellular carcinoma cancer-associated fibroblasts affects cancer cell phenotypes and tumor growth. Cell Oncol (Dordr) 2022; 45:1435-1449. [PMID: 36435866 PMCID: PMC9747837 DOI: 10.1007/s13402-022-00730-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/08/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND CXCL11 has been reported to be up-regulated in hepatocellular carcinoma (HCC) tissues and cancer-associated fibroblasts (CAFs), and CAF-secreted CXCL11 has been found to promote HCC cell proliferation and migration. Knowledge on how CAFs promote HCC progression is imperative for the future design of anti-tumor drugs addressing the high rates of disease recurrence. Herein, we propose a mechanism by which LINC00152 positively regulates CXCL11 expression and, subsequently, HCC cell phenotypes and growth characteristics via miR-205-5p in CAFs. METHODS The expression of LINC00152, miR-205-5p in HCC/non-cancerous tissues, CAFs/NFs and HCC cell lines was determined by RT-qPCR. The CXCL11 expression and secretion were determined by westernblot and ELISA. Different expressions of LINC00152, CXCL11 and miR-205-5p in CAFs were achieved by transfection with corresponding overexpression/knockdown vectors or mimics/inhibitor. The interactions among LINC00152, miR-205-5p and CXCL11 were confirmed by FISH, luciferase, AGO2 and RNA-pulldown assays. Transwell, colony formation and MTT assays were performed to assess the role of CAFs conditioned medium (CM) in HCC cell phenotype. BALB/c nude mice xenografts were used to determine the role of CAFs on HCC growth in vivo. RESULTS We found that in vitro, CM from CAFs transfected with sh-LINC00152 dramatically suppressed HCC cell viability, colony formation and migration, and that CM from CAFs transfected with miR-205-5p inhibitor (CAF-CM (miR-205-5p inhibitor)) exerted opposite effects on HCC cell phenotypes. Exogenous overexpression of CXCL11 in CAFs or CAF-CM (miR-205-5p inhibitor) could partially attenuate the effects of LINC00152 knockdown. In contrast, CM from CAFs transfected with LINC00152 dramatically increased HCC cell viability, colony formation and migration, and CM from CAFs transfected with miR-205-5p mimics (CAF-CM (miR-205-5p mimics)) exerted opposite effects on HCC cell phenotypes. Knockdown of CXCL11 in CAFs or CAF-CM (miR-205-5p mimics) could partially attenuate the effects of LINC00152 overexpression. In vivo, LINC00152 knockdown in CAFs inhibited tumor growth in a mouse model, which could be reversed by CXCL11 overexpression in CAFs. Mechanistically, we found that LINC00152 could act as a ceRNA to counteract miR-205-5p-mediated suppression on CXCL11 by directly binding to miR-205-5p and the 3'UTR of CXCL11. CONCLUSION Our data indicate that a LINC00152/miR-205-5p/CXCL11 axis in HCC CAFs can affect the proliferative and migrative abilities of HCC cells in vitro and HCC tumor growth in vivo.
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Affiliation(s)
- Gao Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Zhang-Fu Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Jian Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Bao-Ye Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Pei-Yun Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Cheng Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Ruo-Yu Guan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Zhu-Tao Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Yong Yi
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
| | - Shuang-Jian Qiu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute and Biomedical Research Center, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032 Shanghai, People’s Republic of China
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Leone V, Ali A, Weber A, Tschaharganeh DF, Heikenwalder M. Liver Inflammation and Hepatobiliary Cancers. Trends Cancer 2021; 7:606-623. [PMID: 33674229 DOI: 10.1016/j.trecan.2021.01.012] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 12/17/2020] [Accepted: 01/28/2021] [Indexed: 02/06/2023]
Abstract
Immune regulation has an important role in cancer development, particularly in organs with continuous exposure to environmental pathogens, such as the liver and gastrointestinal tract. Chronic liver inflammation can lead to the development of hepatobiliary cancers, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or combined HCC (cHCC)-CCA. In this review, we discuss the link between oxidative stress and the hepatic immune compartments, as well as how these factors trigger hepatocyte damage, proliferation, and eventually cancer initiation and its sustainment. We further give an overview of new anticancer therapies based on immunomodulation.
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Affiliation(s)
- Valentina Leone
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Research Unit Radiation Cytogenetics, Helmholtz Zentrum München Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany
| | - Adnan Ali
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Achim Weber
- Department of Pathology and Molecular Pathology, Institute of Molecular Cancer Research (IMCR), University Zurich and University Hospital Zurich, 8091 Zurich, Switzerland
| | - Darjus Felix Tschaharganeh
- Helmholtz-University Group Cell Plasticity and Epigenetic Remodeling, German Cancer Research Center (DKFZ) and Institute of Pathology University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
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3
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Siyin ST, Liu T, Li W, Yao N, Xu G, Qu J, Chen Y. A prospective follow-up study of the relationship between high-sensitivity C-reactive protein and primary liver cancer. BMC Cancer 2020; 20:1168. [PMID: 33256656 PMCID: PMC7706276 DOI: 10.1186/s12885-020-07665-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 11/19/2020] [Indexed: 02/07/2023] Open
Abstract
Background Competing risk method has not been used in a large-scale prospective study to investigate whether increased levels of high-sensitivity C-reactive protein (hs-CRP) elevate the risk of primary liver cancer (PLC). Our study aims to prospectively investigate the relationship between hs-CRP and new-onset PLC. Methods and results Ninety-five thousand seven hundred fifty-nine participants without the diagnosis of PLC, and who had their demographic characteristics and biochemical parameters recorded, were analyzed from the Kailuan Cohort study. Cox proportional hazards regression models and competing risk regression models were used to evaluate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) of PLC. During a median follow-up of 11.07 years, 357 incidental PLC cases were identified over a total of 1,035,039 person-years. The multivariable HRs (95%CI) for the association of hs-CRP of 1–3 mg/L group and hs-CRP>3 mg/L with PLC were 1.07(0.82 ~ 1.38), 1.51(1.15 ~ 1.98) in a Cox proportional hazard regression analysis adjusted for other potential confounders. In the cause-specific hazard model, the multivariable HRs (95%CI) for the association of hs-CRP of 1–3 mg/L group and hs-CRP>3 mg/L with PLC were 1.06(0.81 ~ 1.40), 1.50(1.14 ~ 1.99). Similar results were also observed in the sub-distribution hazard function model with corresponding multivariate HRs (95%CI) of 1.05(0.80 ~ 1.40), 1.49(1.13 ~ 1.98) in hs-CRP of 1–3 mg/L group and hs-CRP>3 mg/L group, respectively. Conclusions This prospective study found a significant association of higher levels of hs-CRP with new-onset PLC. The main clinical implications would be an increased awareness of hs-CRP and its correlation to the risk of PLC. This study should be a steppingstone to further research on chronic inflammation and PLC. Trial registration Registration number:ChiCTR–TNRC–11001489.
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Affiliation(s)
- Sarah Tan Siyin
- Department of General Surgery, Aerospace Center Hospital, Yuquan Road 13, Haidian District, Beijing, 100089, China
| | - Tong Liu
- Department of General Surgery, Aerospace Center Hospital, Yuquan Road 13, Haidian District, Beijing, 100089, China
| | - Wenqiang Li
- Department of General Surgery, Aerospace Center Hospital, Yuquan Road 13, Haidian District, Beijing, 100089, China
| | - Nan Yao
- Department of General Surgery, Aerospace Center Hospital, Yuquan Road 13, Haidian District, Beijing, 100089, China
| | - Guoshuai Xu
- Department of General Surgery, Aerospace Center Hospital, Yuquan Road 13, Haidian District, Beijing, 100089, China
| | - Jun Qu
- Department of General Surgery, Aerospace Center Hospital, Yuquan Road 13, Haidian District, Beijing, 100089, China.
| | - Yajun Chen
- Department of General Surgery, Beijing Children's Hospital, National Center for Children's Health, Beijing, China
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Fan M, Qian N, Dai G. Expression and prognostic significance of doublecortin-like kinase 1 in patients with hepatocellular carcinoma. Oncol Lett 2017; 14:7529-7537. [PMID: 29344199 DOI: 10.3892/ol.2017.7082] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 07/20/2017] [Indexed: 12/17/2022] Open
Abstract
Doublecortin-like kinase 1 (DCLK1), a putative cancer stem cell marker in intestinal and pancreatic tumors, is associated with tumor pathogenesis and progression, and poor survival outcomes in numerous types of cancer. However, DCLK1 expression and its prognostic value remain unclear in hepatocellular carcinoma (HCC). In the present study, the expression of DCLK1 was assessed using immunohistochemistry in 96 resected HCC and 68 adjacent tissue specimens. The staining intensity and the percentage of stained cells were scored on a scale of 0-3 and 0-4, respectively. Tissue was defined as positive for DCLK1 if the composite multiple score was >3. Cytoplasmic expression of DCLK1 was observed in HCC and adjacent tissue specimens with an expression rate of 81% (78/96) and 74% (50/68), respectively; the median score was 4.6 and 3.9, respectively, and no statistically significant difference was observed between HCC and adjacent tissues (P=0.087). DCLK1 expression was positively associated with intrahepatic metastasis (P=0.035). Furthermore, univariate analysis revealed that DCLK1 expression was significantly associated with poor disease-free survival (DFS) and overall survival (P=0.024 and 0.034). Multivariate analysis also demonstrated that DCLK1 expression was an independent prognostic factor for DFS in HCC (P=0.019; hazard ratio, 1.546; 95% confidence interval, 1.330-1.725). Stratified Kaplan-Meier survival curves revealed that DCLK1 expression predicted poorer DFS with respect to positivity for three characteristics: Portal venous metastasis, intrahepatic metastasis, and cirrhosis (P=0.020, P=0.007 and P=0.017, respectively). Collectively, the results of the present study suggested that DCLK1, functioning as a tumor promoter, is frequently overexpressed in HCC, and that DCLK1 expression is associated with poor DFS in patients with HCC. DCLK1 may represent a promising therapeutic target in HCC and requires further study.
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Affiliation(s)
- Mengjiao Fan
- Department of Oncology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
| | - Niansong Qian
- Department of Oncology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
| | - Guanghai Dai
- Department of Oncology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
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Epigenetic mechanisms regulating the development of hepatocellular carcinoma and their promise for therapeutics. Hepatol Int 2016; 11:45-53. [PMID: 27271356 DOI: 10.1007/s12072-016-9743-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 05/17/2016] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers around the globe and third most fatal malignancy. Chronic liver disorders such as chronic hepatitis and liver cirrhosis often lead to the development of HCC. Accumulation of genetic and epigenetic alterations are involved in the development of HCC. Genetic research sparked by recent developments in next generation sequencing has identified the frequency of genetic alterations that occur in HCC and has led to the identification of genetic hotspots. Emerging evidence suggests that epigenetic aberrations are strongly associated with the initiation and development of HCC. Various important genes encoding tumor suppressors including P16, RASSF1A, DLC-1, RUNX3 and SOCS-1 are targets of epigenetic dysregulation during the development of HCC. The present review discusses the importance of epigenetic regulations including DNA methylation, histone modification and microRNA mediated regulation of gene expression during tumorigenesis and their use as disease biomarkers. Furthermore, these epigenetic alterations have been discussed in relationship with promising therapeutic perspectives for HCC and related cancers.
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6
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Sureban SM, Madhoun MF, May R, Qu D, Ali N, Fazili J, Weygant N, Chandrakesan P, Ding K, Lightfoot SA, Houchen CW. Plasma DCLK1 is a marker of hepatocellular carcinoma (HCC): Targeting DCLK1 prevents HCC tumor xenograft growth via a microRNA-dependent mechanism. Oncotarget 2015; 6:37200-15. [PMID: 26468984 PMCID: PMC4741924 DOI: 10.18632/oncotarget.5808] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 10/06/2015] [Indexed: 01/07/2023] Open
Abstract
Tumor stem cell marker Doublecortin-like kinase1 (DCLK1) is upregulated in several solid tumors. The role of DCLK1 in hepatocellular carcinoma (HCC) is unclear. We immunostained tissues from human livers with HCC, cirrhosis controls (CC), and non-cirrhosis controls (NCC) for DCLK1. Western blot and ELISA analyses for DCLK1 were performed with stored plasma samples. We observed increased immunoreactive DCLK1 in epithelia and stroma in HCC and CCs compared with NCCs, and observed a marked increase in plasma DCLK1 from patients with HCC compared with CC and NCC. Analysis of the Cancer Genome Atlas' HCC dataset revealed that DCLK1 is overexpressed in HCC tumors relative to adjacent normal tissues. High DCLK1-expressing cells had more epithelial-mesenchymal transition (EMT). Various tumor suppressor miRNAs were also downregulated in HCC tumors. We evaluated the effects of DCLK1 knockdown on Huh7.5-derived tumor xenograft growth. This was associated with growth arrest and a marked downregulation of cMYC, and EMT transcription factors ZEB1, ZEB2, SNAIL, and SLUG via let-7a and miR-200 miRNA-dependent mechanisms. Furthermore, upregulation of miR-143/145, a corresponding decrease in pluripotency factors OCT4, NANOG, KLF4, and LIN28, and a reduction of let-7a, miR-143/145, and miR-200-specific luciferase activity was observed. These findings suggest that the detection of elevated plasma DCLK1 may provide a cost-effective, less invasive tool for confirmation of clinical signs of cirrhosis, and a potential companion diagnostic marker for patients with cirrhosis and HCC. Our results support evaluating DCLK1 as a biomarker for detection and as a therapeutic target for eradicating HCC.
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MESH Headings
- Animals
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Carcinoma, Hepatocellular/blood
- Carcinoma, Hepatocellular/enzymology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Cell Line, Tumor
- Cell Proliferation
- Databases, Genetic
- Doublecortin-Like Kinases
- Gene Expression Regulation, Neoplastic
- Gene Knockdown Techniques
- Genetic Therapy/methods
- Humans
- Intracellular Signaling Peptides and Proteins/blood
- Intracellular Signaling Peptides and Proteins/genetics
- Kruppel-Like Factor 4
- Liver Cirrhosis/blood
- Liver Cirrhosis/enzymology
- Liver Neoplasms/blood
- Liver Neoplasms/enzymology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Mice, Nude
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Neoplastic Stem Cells/enzymology
- Neoplastic Stem Cells/pathology
- Phenotype
- Protein Serine-Threonine Kinases/blood
- Protein Serine-Threonine Kinases/genetics
- RNA Interference
- RNAi Therapeutics
- Retrospective Studies
- Signal Transduction
- Time Factors
- Transcription Factors/genetics
- Transcription Factors/metabolism
- Transfection
- Tumor Burden
- Up-Regulation
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Sripathi M. Sureban
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, USA
| | - Mohammad F. Madhoun
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
| | - Randal May
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
| | - Dongfeng Qu
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, USA
| | - Naushad Ali
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, USA
| | - Javid Fazili
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
| | - Nathaniel Weygant
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Parthasarathy Chandrakesan
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, USA
| | - Kai Ding
- Department of Biostatistics & Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Stanley A. Lightfoot
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Courtney W. Houchen
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- Department of Veterans Affairs Medical Center, Oklahoma City, OK 73104, USA
- The Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK 73104, USA
- COARE Biotechnology Inc., Oklahoma City, OK 73104, USA
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Lake-Bakaar G, Ahmed M, Evenson A, Bonder A, Faintuch S, Sundaram V. Hagen-Poiseuille’s law: The link between cirrhosis, liver stiffness, portal hypertension and hepatic decompensation. World J Hepatol 2015; 7:28-32. [PMID: 25624993 PMCID: PMC4295190 DOI: 10.4254/wjh.v7.i1.28] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Revised: 07/22/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
The onset of hepatic decompensation in cirrhosis heralds an accelerated downhill course with poor outcome. The sole predictor of this decompensation in cirrhosis is increased hepatic vein to portal vein gradient hepatic venous pressure gradient (HVPG). Surrogate markers of liver function or hepatic reserve appear to be less relevant. The hepatic sinusoids become less elastic and more rigid as liver fibrosis and cirrhosis progress. We propose that the Hagen-Poiseuille’s law, which applies to rigid, but not elastic vessels, determines the pressure-flow characteristics in the sinusoids. In the rigid cirrhotic liver, HVPG rises dramatically with any change in net surface area or radius, r4 of the vasculature that follows surgical resection. This review relates liver stiffness to the risk of decompensation in patients with cirrhosis. The liver has a unique dual blood supply comprising a low pressure portal vein and high pressure hepatic artery. We compare the complexity of autoregulation in the normal elastic liver with that in the rigid cirrhotic liver. Therapeutic modalities to reduce portal pressure may reduce the risk of hepatic decompensation and improve outcomes in cirrhosis.
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Abstract
Hepatocellular carcinoma (HCC) is the most common histologic type of primary liver cancer, accounting for between 85% and 90% of these malignancies. The overall prognosis of patients with liver cancer is poor, and an understanding of this disease and its risk factors is crucial for screening at-risk individuals, early recognition, and timely diagnosis. Most HCCs arise in the background of chronic liver disease caused by hepatitis B virus, hepatitis C virus, and chronic excessive alcohol intake. These underlying causes are characterized by marked variations in geography, gender, and other well-documented risk factors, some of which are potentially preventable.
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Affiliation(s)
- Kelly J Lafaro
- Department of Surgery, Johns Hopkins Hospital, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Blalock 688, Baltimore, MD 21287, USA
| | - Aram N Demirjian
- Department of Surgery, University of California-Irvine, 333 City Boulevard West, Suite 1205, Orange, CA 92868, USA
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, Johns Hopkins Hospital, 600 North Wolfe Street, Blalock 688, Baltimore, MD 21287, USA.
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9
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Lake-Bakaar G, Ahmed M, Evenson A, Bonder A, Faintuch S, Sundaram V. Management of Hepatocellular Carcinoma in Cirrhotic Patients with Portal Hypertension: Relevance of Hagen-Poiseuille's Law. Liver Cancer 2014; 3:428-38. [PMID: 26280004 PMCID: PMC4531425 DOI: 10.1159/000343871] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Hepatic decompensation in cirrhosis heralds an accelerated course with poor survival. An increase in hepatic venous pressure gradient (HVPG), rather than surrogate tests of liver function, appears to be the sole predictor of decompensation after surgical resection. We propose that hepatic sinusoidal walls become less elastic as cirrhosis progresses. Decompensation signals the development of increased vessel wall rigidity. The pressure-flow characteristics then become subject to Hagen-Poiseuille's law, which applies only to rigid, cylindrical vessels. Thereafter, HVPG rises exponentially (by a factor inversely proportional to the fourth power of the net radius of functional sinusoidal vessels, 1/r(4), at any given hepatic blood flow rate. This review attempts to correlate liver stiffness, risk of decompensation and outcomes from hepatocellular carcinoma (HCC) in patients with cirrhosis. SUMMARY We compare the complexity of autoregulation in the normal elastic liver, which has a unique dual blood supply, with that in the rigid cirrhotic liver. We also review, in the context of background liver cirrhosis, the management of HCC which is in essence, a solid mass of unorganized cells that exacerbates liver stiffness. We discuss the differential effects of various therapeutic modalities such as liver transplantation, loco-regional therapy and drugs on HCC outcomes, based on their effects on HVPG. KEY MESSAGES Increased hepatic artery supply, or the hepatic artery buffer response, may be the only available method for autoregulation or maintenance of hepatic blood flow in the cirrhotic liver. In HCC, loco-regional therapies, including partial resection of the cirrhotic liver, can exacerbate portal hypertension by increasing blood flow within the remnant organ. We conclude that studies of HVPG reduction as part of HCC management may be beneficial and are warranted.
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Affiliation(s)
- Gerond Lake-Bakaar
- *Gerond Lake-Bakaar, MD, PhD, Liver Tumor Center, Department of Medicine, Beth Israel Deaconess, Medical Center, Harvard Medical School, 110 Francis Street, Suite 7A-055, Boston, MA 02215 (USA), Tel. +1 617 632 9838, E-Mail
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10
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Wang Q, Zhai YY, Dai JH, Li KY, Deng Q, Han ZG. SAMD9L inactivation promotes cell proliferation via facilitating G1-S transition in hepatitis B virus-associated hepatocellular carcinoma. Int J Biol Sci 2014; 10:807-16. [PMID: 25076857 PMCID: PMC4115192 DOI: 10.7150/ijbs.9143] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Accepted: 05/19/2014] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant cancer with poor prognosis, and driver genes harboring genetic lesions and/or expression dysregulation contribute to hepatocarcinogenesis. Sterile Alpha Motif Domain-containing 9-like (SAMD9L) was a novel identified mutated gene in our previous study on exome sequencing of hepatitis B virus (HBV)-associated HCC, but its expression and role in HCC remain unknown. Here, we demonstrated that SAMD9L was frequently inactivated by somatic mutations, and that its expression was deregulated in HCC patients with hepatitis B virus (HBV) infection. SAMD9L knockdown significantly promoted cell proliferation, colony formation of SK-hep-1, QGY-7701, BEL-7721 and MHCC-97H HCC cells. Furthermore, SK-hep-1 and MHCC-97H cells with stable SAMD9L knockdown exhibited enhanced tumorigenicity in athymic mice. Interestingly, SAMD9L silence facilitated G1-S transition of cell cycle progression and led to the elevated activity of Wnt/β-catenin pathway. Collectively, these findings highlight a novel tumor-suppressive role of SAMD9L inactivation by somatic mutation and decreased expression in human HBV-related HCC.
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Affiliation(s)
- Qun Wang
- 1. Key Laboratory of Systems Biomedicine (Ministry of Education) of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China ; 2. Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China
| | - Yang-Yang Zhai
- 2. Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China
| | - Ji-Hong Dai
- 2. Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China
| | - Kun-Yu Li
- 2. Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China
| | - Qing Deng
- 2. Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China
| | - Ze-Guang Han
- 1. Key Laboratory of Systems Biomedicine (Ministry of Education) of Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China ; 2. Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China ; 3. Shanghai Center for systems Biomedicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China
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A current update on the rule of alternative and complementary medicine in the treatment of liver diseases. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:321234. [PMID: 24109491 PMCID: PMC3784269 DOI: 10.1155/2013/321234] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Accepted: 08/02/2013] [Indexed: 02/05/2023]
Abstract
There is a vast body of knowledge which is ever-increasing about the treatment of liver disease with alternative and complementary medicine for which hundreds of thousands of literatures have been documented. Liver disease is a general term. This term covers all the potential problems that cause the liver to fail to perform its specified operations. Liver disease has a variety of presentations and causes a great public health problem worldwide which threatens the wellness of billions of people. Incidences of many types of liver disease are currently rising. Although there is still a debate about the entity of alternative and complementary medicine, it is now widely used and it is improving. And it covers the shortages and compensates for the weaknesses of conventional methods in the treatment of liver diseases. Alternative and complementary medicine for liver diseases provides benefits by regulating immunity, controlling disease progression, improving quality of life, and prolonging survival. This paper reviews the increasing interest and growing research into alternative and complementary medicine for liver diseases, with a look at the rough classification, principle of management, evidence-based applications, and issues for prescription and perspectives.
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Park SJ, Lee JR, Jo MJ, Park SM, Ku SK, Kim SC. Protective effects of Korean red ginseng extract on cadmium-induced hepatic toxicity in rats. J Ginseng Res 2013; 37:37-44. [PMID: 23717155 PMCID: PMC3659623 DOI: 10.5142/jgr.2013.37.37] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2012] [Revised: 07/11/2012] [Accepted: 08/29/2012] [Indexed: 11/18/2022] Open
Abstract
Korean red ginseng is known to regulate the immune system and help the body struggle infection and disease. Cadmium is widely distributed in the environment due to its use in industry. Exposure to cadmium is problematic causing organ dysfunction. This study was conducted to evaluate the protective effect of Korean red ginseng extract (RGE) against cadmium-induced hepatotoxicity in rats. In experiments, animals were orally administrated with RGE (25, 50 mg/kg) for 7 d and then intravenously injected with cadmium (CdCl2, 4 mg/kg) to induce acute hepatotoxicity. Cadmium caused the elevated levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase in serum. In contrast, pretreatment with RGE significantly reduced those serum indexes related with liver damage. In histopathological analysis, RGE decreased the centrilobular necrosis around central veins and the peripheral hemorrhage around portal triads. Moreover, RGE restored the deficit in hepatic glutathione level resulting from cadmium treatment. RGE also inhibited the increase in the expression of Bad, a representative apoptosis marker protein, induced by cadmium treatment. Collectively, these results demonstrate that RGE can reduce the cadmium-induced hepatic toxicity, partly via anti-oxidative and anti-apoptotic process.
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Affiliation(s)
- Sook Jahr Park
- College of Oriental Medicine, Daegu Haany University, Gyeongsan 712-715, Korea ; Medical Research Center for Globalization of Herbal Formulation, Daegu Haany University, Gyeongsan 712-715, Korea
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Palliyaguru DL, Wu F. Global geographical overlap of aflatoxin and hepatitis C: controlling risk factors for liver cancer worldwide. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2013; 30:534-40. [PMID: 23281740 DOI: 10.1080/19440049.2012.751630] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
About 85% of hepatocellular carcinoma (HCC, liver cancer) cases occur in low-income countries, where the risk factors of dietary aflatoxin exposure and chronic hepatitis B and C (HBV and HCV) viral infection are common. While studies have shown synergism between aflatoxin and HBV in causing HCC, much less is known about whether aflatoxin and HCV synergise similarly. From an exposure perspective, it was examined whether there is a geographical overlap in populations worldwide exposed to high dietary aflatoxin levels and with high HCV prevalence. While HCV is one of the most important risk factors for HCC in high-income nations (where aflatoxin exposure is low), it is found that HCV prevalence is much higher in Africa and Asia, where aflatoxin exposure is also high. However, within a given world region, there are some inconsistencies regarding exposure and cancer risk. Therefore, there is a need to control risk factors such as aflatoxin and hepatitis viruses in a cost-effective manner to prevent global HCC, while continuing to evaluate biological mechanisms by which these risk factors interact to increase HCC risk.
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Affiliation(s)
- D L Palliyaguru
- Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA
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Martin M, Herceg Z. From hepatitis to hepatocellular carcinoma: a proposed model for cross-talk between inflammation and epigenetic mechanisms. Genome Med 2012; 4:8. [PMID: 22293089 PMCID: PMC3334556 DOI: 10.1186/gm307] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Inflammation represents the body's natural response to tissue damage; however, chronic inflammation may activate cell proliferation and induce deregulation of cell death in affected tissues. Chronic inflammation is an important factor in the development of hepatocellular carcinoma (HCC), although the precise underlying mechanism remains unknown. Epigenetic events, which are considered key mechanisms in the regulation of gene activity states, are also commonly deregulated in HCC. Here, we review the evidence that chronic inflammation might deregulate epigenetic processes, thus promoting oncogenic transformation, and we propose a working hypothesis that epigenetic deregulation is an underlying mechanism by which inflammation might promote HCC development. In this scenario, different components of the inflammatory response might directly and indirectly induce changes in epigenetic machineries ('epigenetic switch'), including those involved in setting and propagating normal patterns of DNA methylation, histone modifications and non-coding RNAs in hepatocytes. We discuss the possibility that self-reinforcing cross-talk between inflammation and epigenetic mechanisms might amplify inflammatory signals and maintain a chronic state of inflammation culminating in cancer development. The potential role of inflammation-epigenome interactions in the emergence and maintenance of cancer stem cells is also discussed.
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Affiliation(s)
- Marion Martin
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon CEDEX 08, France
| | - Zdenko Herceg
- Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon CEDEX 08, France
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