Identification and Characterization of Molecular Targets in Hepatocellular Carcinoma PDF Download

Author: Vinay Kumar
Publisher: Frontiers Media SA
ISBN: 2832526276
Category : Science
Languages : en
Pages : 327

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Book Description
the field of oncology and is the most common form of liver cancer. In some cases, HCC can be treated through surgery and ablations but can be extended to a full transplant. Risk factors for HCC have been elucidated in previous years, linking hepatitis viruses, diabetes, and alcohol-dependent conditions to the pathogenesis of HCC. Given the prevalence of HCC in global populations (currently >800,000 new cases per year, and rising), there is a requirement to identify molecular targets in HCC and develop new therapeutic strategies to manage and treat HCCs. New technologies and techniques, including gene sequencing, bioinformatics, and liquid biopsy, have helped identify molecular and genetic players involved in the development of HCC. As such, a comprehensive genetic/immune signature of HCC would be invaluable in the development of new therapeutics and treatment strategies, as well as early identification and management of HCC. There are currently various trials that implement a combination of already approved drugs to better the prognosis of patients suffering from HCC. There is, however, still room for improvement, and as our understanding of the various factors involved in HCC improves, so will the prognosis of patients suffering from HCC globally. This Research Topic aims to highlight the molecular and genetic targets that lead to the progression of Hepatocellular Carcinoma. We welcome Original Research, Reviews, and other article types.

Author: Yujin Hoshida
Publisher: Springer
ISBN: 3030215407
Category : Medical
Languages : en
Pages : 366

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Book Description
This book provides a comprehensive overview of the current limitations and unmet needs in Hepatocellular Carcinoma (HCC) diagnosis, treatment, and prevention. It also provides newly emerging concepts, approaches, and technologies to address challenges. Topics covered include changing landscape of HCC etiologies in association with health disparities, framework of clinical management algorithm, new and experimental modalities of HCC diagnosis and prognostication, multidisciplinary treatment options including rapidly evolving molecular targeted therapies and immune therapies, multi-omics molecular characterization, and clinically relevant experimental models. The book is intended to assist collaboration between the diverse disciplines and facilitate forward and reverse translation between basic and clinical research by providing a comprehensive overview of relevant areas, covering epidemiological trend and population-level patient management strategies, new diagnostic and prognostic tools, recent advances in the standard care and novel therapeutic approaches, and new concepts in pathogenesis and experimental approaches and tools, by experts and opinion leaders in their respective fields. By thoroughly and concisely covering whole aspects of HCC care, Hepatocellular Carcinoma serves as a valuable reference for multidisciplinary readers, and promotes the development of personalized precision care strategies that lead to substantial improvement of disease burden and patient prognosis in HCC.

Author: 盧綽琳
Publisher:
ISBN:
Category : Liver
Languages : en
Pages : 273

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Author: 洪偉翔
Publisher:
ISBN:
Category :
Languages : en
Pages : 98

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Author: Jian Wang
Publisher:
ISBN: 9781361294291
Category :
Languages : en
Pages :

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This dissertation, "Identification and Characterization of N-terminal Kinase Like Protein in Hepatocellular Carcinoma" by Jian, Wang, 王健, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. DOI: 10.5353/th_b4703637 Subjects: Tumor proteins Liver - Cancer - Molecular aspects

Author: Ming Liu
Publisher: Open Dissertation Press
ISBN: 9781361333235
Category :
Languages : en
Pages :

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This dissertation, "Identification and Characterization of Novel Genetic Alterations in the Progression of Hepatocellular Carcinoma" by Ming, Liu, 劉銘, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies worldwide with very poor prognosis. It is generally believed that accumulation of irreversible alterations in critical oncogenes and tumor suppressor genes during the long-term inflammation finally leads to the hepatocellular pathogenesis. Although under intensive investigation, the molecular pathogenesis of HCC still remains to be further elucidated. In this study, we aimed to identify novel genetic alterations critical to the pathogenesis of HCC, especially in hot regions with recurrent chromosomal instability. Amplification of broad regions of 8q is one of the most frequent genetic alterations in HCC, suggesting the existence of oncogenes in addition to MYC at 8q24. By screening the publicly available microarray database and clinical samples, we found frequent amplification and overexpression of Serum and Glucocorticoid Kinase 3 (SGK3) in clinical HCC specimens, and SGK3 genomic activation was significantly associated with poor outcome of HCC patients. Functional assays revealed that SGK3 could increase G1/S cell cycle progression, cell survival, clonogenicity, anchorage-independent growth, and tumor formation in nude mice. We provided evidences that SGK3 could promote HCC growth and survival through inactivating GSK3-β and BAD respectively. We also found that expression of SGK3, which like AKT is activated by PI3K/PDK1, has more significance than overexpression of AKT in predicting poor outcome of HCC patients. Our findings suggested the existence of an AKT-independent SGK3 pathway, which may function in parallel with AKT pathway in the pathogenesis of HCC. In addition to large chromosomal alterations, small changes in nucleotides may also make substantial contributions to carcinogenesis. Recent advances in high-throughput deep sequencing technology have provided a powerful tool to understand the whole cancer transcriptome and identify novel genetic alterations related to cancer progression. In this study, we identified a high proportion of allele imbalance in genes related to cellular stress response by sequencing the whole transcriptome of 3 paired HCC tissues. A novel nucleotide variation which resulted in a R438H amino acid change was identified in the coding region of the gene Oxidative Stress Induced Growth Inhibitor 1 (OSGIN1), and the variant 438H form of OSGIN1 was found to be specifically retained in the tumor tissues in a cohort of HCC patients. OSGIN1 was found to be closely associated with chemotherapeutic reagents and exhibited strong tumor suppressive function in HCC by directly inducing cell apoptosis. The wild type OSGIN1 was found to have stronger tumor suppressive function than the variant allele, and this might be due to their different ability to localize to mitochondria. The significantly decreased basal apoptotic index in HCC patients carrying OSGIN1 variant allele and their poor prognosis further suggested that the specific retention of 438H OSGIN1 might be important in HCC progression. In summary, we found a frequently amplified oncogenic SGK3 signaling pathway, as well as the allele-specific imbalance of tumor suppressive OSGIN1 in the pathogenesis of HCC. Further characterization of their mechanisms in hepatocarcinogenesis may help provide novel prognostic biomarkers and therapeutic targets in HCC treatment. DOI: 10.5353/th_b5177316

Author: Marina Simon Coma
Publisher:
ISBN:
Category :
Languages : en
Pages : 219

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Malignant tumors in children and adolescents are one of the leading causes of death from disease in this population despite being rare events. The main liver tumor in children is Hepatoblastoma (HB) representing two thirds of the total while pediatric Hepatocellular Carcinoma (pHCC) is rarer than HB and is usually diagnosed in older patients. Patient survival at 5 years is higher than 75% for HB and less than 30% for pHCC. At molecular level, 2 different subclasses of HBs have been described based on a 16-gene signature, C1 and C2, being the latest more aggressive. Nowadays patient stratification is based only in clinical and pathological parameters. For this reason, the identification of prognostic markers easy to apply at the clinical practice is mandatory in order to better stratify patients and diminish the side effects of chemotherapy treatment, moving towards a more personalized medicine. The proteomic profile of 16HBs and 8 paired normal liver (NL) tissue was obtained by 2 different techniques, two-dimensional gel electrophoresis and label-free LC-MS. The differential expressed proteins were validated by western blot (WB) in the same patients and the final protein signature was validated by immunohistochemistry in additional 144 patients. Furthermore, RNA sequencing and copy number variation analysis were performed in 31 HB samples, 11 patient-derived xenografts (PDXs) and 5 pHCC. Results were validated by Sanger sequencing, droplet digital PCR or real time PCR and correlated with clinical features. Two hundred and thirty proteins were identified as deregulated in aggressive C2 tumors and 8 of them were selected and validated by WB considering also their expression in NL. After WB, 2 proteins were found significantly upregulated in C2 tumors while 1 was downregulated. A score was calculated for each protein and biomarkers 1 and 2 were considered altered when their staining was at least 2-fold higher than the NL while the biomarker 3 was considered as altered when no staining was observed. The 3-protein signature was defined by the number of altered biomarkers in each tumor and was highly correlated with patient survival and complementary to the current clinical stratification. RNA-sequencing data revealed that fusion proteins are rare events in HB as they were found in only 2% of patients. Mutational analysis allowed us to identify mutations in CTNNB1 (30%), NFE2L2 (7%) and EPHB4 (7%). Interestingly we identified a downregulation of the RNA editing which is correlated with patient outcome. The copy number variation analysis showed that gains are more frequent than losses in HB tumors and that PDXs maintain 78% of the aberrations, being a good model for the study of HB. In contrast, pHCC are characterized by more aberrations than HB and mainly losses. Thus, we stablished a molecular classification that includes 3 HB types: stable (no big CNVs), gains-enriched and losses-enriched classes. This classification is correlated with event-free survival, CTNNB1 mutations and the expression of stem cell markers. As a result of this thesis, we stablished a 3-protein signature that could be easily applied at the clinical practice and increased the molecular knowledge of childhood liver tumors.

Author: Yan Li
Publisher: Open Dissertation Press
ISBN: 9781361003824
Category :
Languages : en
Pages :

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This dissertation, "Identification and Characterization of Two Oncogenes SPOCK1 and AZIN1 in Hepatocellular Carcinoma" by Yan, Li, 李妍, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Hepatocellular carcinoma (HCC), which constitutes 75%-80% of primary liver cancer, is one of the most common malignancies worldwide. Hepatocarcinogenesis is a complicated and slow process accumulating multiple genetic and epigenetic alterations. In spite of its prolonged pre-malignant stage, HCC is usually diagnosed late and of high aggressiveness. A better understanding of the genetic and epigenetic changes during HCC development and progression is of great importance to early diagnosis and treatment of HCC. Gain of chromosome 1q21 is one of most frequent genetic alteration in HCC and chromodomain helicase DNA binding protein 1-like (CHD1L) was recently identified to be responsible for this amplification. As a family member of SNF-2 like transcription factors, CHD1L plays an important role in HCC development via regulation of various downstream targets. In this study, a novel oncogene, sparc/osteonectin, cwcv and kazal-like domains proteoglycan 1 (SPOCK1), was identified as a CHD1L target. CHD1L protein directly bound to the promoter region (nt -1662 to +34) of SPOCK1 and activated its transcription. Clinically, overexpression of SPOCK1 was detected in 60% of human HCC samples and was significantly associated with advanced clinical stage (P=0.020), shorter overall survival (P=0.011) and poorer disease-free survival of patients (P=0.039). Functionally, the ectopic expression of SPOCK1 in HCC cells conferred strong tumorigenic ability, while shRNA-mediated SPOCK1 silencing abolished this effect. Further study showed that the SPOCK1-enhanced cell survival could be attributed to its anti-apoptotic effects. SPOCK1 could suppress HCC cell apoptosis through the activation of AKT and subsequent inhibition of the (cytochrome c)-(caspase-9)-(caspase-3) pathway. In addition to its tumorigenic roles, the overexpression of SPOCK1 in HCC cells conferred strong metastatic ability via MMP9-mediated extracellular matrix remodeling. In addition to genetic alterations, epigenetic changes also get increasing attentions due to their profound effects on gene activity and expression. A-to-I RNA editing is a post-transcriptional epigenetic modification which converts a site-selective adenosine nucleotide into inosine. The importance of RNA editing has long been underestimated because most of RNA editing modifications occur in a subtle way. The next-generation sequencing provides enough depth to unravel this mystery. The transcriptome sequencing data obtained from this study identified an A-to-I RNA editing at codon 367 (Ser→Gly) of antizyme inhibitor 1 (AZIN1). A high modification rate of AZIN1 was found to be prevalent in HCC specimens and closely associated with HCC pathogenesis. Adenosine deaminase acting on RNA-1 (ADAR1), but not ADAR2 or ADAR3, was responsible for AZIN1 RNA editing. This recoding editing event conferred "gain-of-function" phenotypes as manifested by augmented tumorigenic capabilities and higher aggressive potentials. Compared with wild-type AZIN1 protein, the edited form possessed stronger affinity to antizyme. As a result, edited AZIN1 demonstrated higher protein stability and ensuing neutralization of the antizyme-mediated degradation of ODC and CCND1 oncoproteins. The rescued ODC and CCND1 robustly accelerated cell proliferation thereby promoting HCC development. In conclusion, two novel molecular mechanisms, (CHD1L)-(SPOCK1)-(AKT) and (ADAR1)-(edited A

Author: Tim F. Greten
Publisher: Springer
ISBN: 9783319879116
Category : Medical
Languages : en
Pages : 0

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In this book we provide insights into liver – cancer and immunology. Experts in the field provide an overview over fundamental immunological questions in liver cancer and tumorimmunology, which form the base for immune based approaches in HCC, which gain increasing interest in the community due to first promising results obtained in early clinical trials. Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death in the United States. Treatment options are limited. Viral hepatitis is one of the major risk factors for HCC, which represents a typical “inflammation-induced” cancer. Immune-based treatment approaches have revolutionized oncology in recent years. Various treatment strategies have received FDA approval including dendritic cell vaccination, for prostate cancer as well as immune checkpoint inhibition targeting the CTLA4 or the PD1/PDL1 axis in melanoma, lung, and kidney cancer. Additionally, cell based therapies (adoptive T cell therapy, CAR T cells and TCR transduced T cells) have demonstrated significant efficacy in patients with B cell malignancies and melanoma. Immune checkpoint inhibitors in particular have generated enormous excitement across the entire field of oncology, providing a significant benefit to a minority of patients.

Author: Wing-Yuen Ho
Publisher:
ISBN: 9781361007440
Category :
Languages : en
Pages :

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This dissertation, "Identification and Characterization of CD90⁺ Cancer Stem Cells in Hepatocellular Carcinoma" by Wing-yuen, Ho, 何永源, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Hepatocellular carcinoma (HCC) is one of the most devastating malignancies worldwide with increasing incidences in both developed and developing countries. Survival rates have not been significantly improved over the past decades in spite of advances in detection and therapies for this disease, suggesting that current treatments may target the wrong cells, and miss the cancer stem cells (CSCs). The cancer stem cell hypothesis presents that tumor formation, proliferation and propagation are driven by a rare subpopulation of chemoresistant CSCs that are not killed by conventional therapies and go on to cause disease relapse. The objective of this study was to identify and characterize CSCs in HCC cell lines and human liver tumor specimens using CD90 as a potential marker. The number of CD90+ cells present in HCC cell lines was found to positively correlate with tumorigenicity potentials. Injection of as few as 2,000 sorted CD90+ cells from HCC cell lines resulted in the formation of tumor nodules in nude mice, whereas no tumors formed for CD90ˉcells in the same model. The tumor xenograft generated by injection of CD90+ cells sorted from previous xenograft in a serial xenotransplantation assay exhibited recapitulation of tumor heterogeneity to original primary tumor and consistent proportion of CD90+ and CD90ˉ cells which demonstrated self-renewal and differentiation capacities of CD90+CSCs. CD45ˉCD90+ cells were detected (0.03%-6.2%) in human liver tumor specimens, but were only present in minute quantities in normal, cirrhotic and non-tumorous tissues. More importantly, CD45ˉCD90+ cells sorted from primary HCC tumor also displayed tumorigenicity, self-renewal and lineage differentiation capacities. CD90+CSCs were found to be more resistant to therapeutic drugs compared to CD90- cells, as reflected by the results of enrichment of the CD90+ CSCs and longer survival rates after chemotherapeutic treatment. The high expression of genes, such as OCT4, MRP3, ABCG2, AKT1, BirC5, BCL2, HA and CD44, in CD90+CSCs may mediate chemoresistance. The majority of CD90+ cells co-expressed CD44, another stem cell marker. Blocking CD44 activities by anti-CD44 antibody increased apoptosis of CD90+ CSCs, sensitized CD90+CSCs to chemotherapeutic drugs in vitro, and decreased tumorigenic and metastatic potentials of CD90+CSCs in vivo, indicating that a therapeutic potential of targeting CD44. However side effects may be problematic due to the endogenous expression of CD44 in healthy tissues and normal lymphocytes. To identify novel gene targets specific to liver CSCs, a sensitive RNA-sequencing (RNA-Seq) technique was used to compare the gene expression profiles between CD90+CSCs sorted from HCC primary tumors and CD90+cells from adjacent non-tumorous tissue (CD90+NTSCs). The up-regulated genes in CD90+CSCs were associated with lipid metabolism, inflammation, and drug resistance. Among the differentially expressed genes, glypican-3 (GPC3) was specifically elevated in CD90+CSCs but not in CD90+NTSCs. Therefore, GPC3 could be a promising gene candidate for HCC therapy as targeting GPC3 should not induce damage to normal liver stem cells. In summary, CD90 is a liver CSCs marker. Identification of CD90+ CSCs in HCC provides new insight into cellular basis of hepatocarcinogenesis, recurrence and metastasis, which opens new avenues for the design of future CSC-targeted therapies. D