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      Gender Disparity of Hepatocellular Carcinoma: The Roles of Sex Hormones

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          Abstract

          Men have a higher incidence of hepatocellular carcinoma (HCC) than women. Epidemiologic and animal studies have suggested that it might be due to the stimulatory effects of androgen and the protective effects of estrogen. Recently, increasing molecular mechanisms underlying the carcinogenic effect of both sex hormones were reported. Knockout of androgen receptor (AR) expression in hepatocytes delayed the development of N′,N′-diethylnitrosamine (DEN)-induced HCC, suggesting the active AR pathway in augmenting the HCC risk. Moreover, an intriguing interaction between the viral protein of hepatitis B virus X protein (HBx) and the androgen pathway was established. HBx can enhance the transcriptional activity of AR in a ligand concentration-dependent manner, mainly through its effects on the c-Src and GSK-3β kinase pathways. The studies from the DEN-induced HCC mouse model further provided a mechanism for the protective role of estrogen in female HCC. Estrogen can protect hepatocytes from malignant transformation via downregulation of IL-6 release from Kupffer cells, a critical process in this mouse model. Intriguingly, suppression of the ERα protein by overexpression of miR-18a, which occurs preferentially in female HCC, was identified as a novel mechanism to block the tumor-protective function of estrogen in female HCC. In conclusion, the current studies demonstrated that the gender disparity of HCC is attributed by both androgen and estrogen sex hormone pathways, with distinct roles in each gender. Therefore, the ligand and the receptor factors of both sex hormones need to be included for assessing the relative risk of HCC patients of each gender.

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          Most cited references48

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          Molecular targeted therapies in hepatocellular carcinoma.

          Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. There is evidence of aberrant activation of several signaling cascades such as epidermal growth factor receptor (EGFR), Ras/extracellular signal-regulated kinase, phosphoinositol 3-kinase/mammalian target of rapamycin (mTOR), hepatocyte growth factor/mesenchymal-epithelial transition factor, Wnt, Hedgehog, and apoptotic signaling. Recently a multikinase inhibitor, sorafenib, has shown survival benefits in patients with advanced HCC. This advancement represents a breakthrough in the treatment of this complex disease and proves that molecular therapies can be effective in HCC. It is becoming apparent, however, that to overcome the complexity of genomic aberrations in HCC, combination therapies will be critical. Phase II studies have tested drugs blocking EGFR, vascular endothelial growth factor/platelet-derived growth factor receptor, and mTOR signaling. No relevant data has been produced so far in combination therapies. Future research is expected to identify new compounds to block important undruggable pathways, such as Wnt signaling, and to identify new oncogenes as targets for therapies through novel high-throughput technologies. Recent guidelines have established a new frame for the design of clinical trials in HCC. Randomized phase II trials with a time-to-progression endpoint are proposed as pivotal for capturing benefits from novel drugs. Survival remains the main endpoint to measure effectiveness in phase III studies. Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Biomarkers and molecular imaging should be part of the trials, in order to optimize the enrichment of study populations and identify drug responders. Ultimately, a molecular classification of HCC based on genome-wide investigations and identification of patient subclasses according to drug responsiveness will lead to a more personalized medicine.
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            Hepatocellular carcinoma: epidemiology, risk factors and pathogenesis.

            Hepatocellular carcinoma (HCC) is the commonest primary malignant cancer of the liver in the world. Given that the burden of chronic liver disease is expected to rise owing to increasing rates of alcoholism, hepatitis B and C prevalence and obesity-related fatty liver disease, it is expected that the incidence of HCC will also increase in the foreseeable future. This article summarizes the international epidemiology, the risk factors and the pathogenesis of HCC, including the roles of viral hepatitis, toxins, such as alcohol and aflatoxin, and insulin resistance.
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              Pivotal role of mTOR signaling in hepatocellular carcinoma.

              The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. We evaluated mTOR signaling in human HCC, as well as the antitumoral effect of a dual-level blockade of the mTOR pathway. The mTOR pathway was assessed using integrated data from mutation analysis (direct sequencing), DNA copy number changes (SNP-array), messenger RNA levels (quantitative reverse-transcription polymerase chain reaction and gene expression microarray), and protein activation (immunostaining) in 351 human samples [HCC (n = 314) and nontumoral tissue (n = 37)]. Effects of dual blockade of mTOR signaling using a rapamycin analogue (everolimus) and an epidermal/vascular endothelial growth factor receptor inhibitor (AEE788) were evaluated in liver cancer cell lines and in a xenograft model. Aberrant mTOR signaling (p-RPS6) was present in half of the cases, associated with insulin-like growth factor pathway activation, epidermal growth factor up-regulation, and PTEN dysregulation. PTEN and PI3KCA-B mutations were rare events. Chromosomal gains in RICTOR (25% of patients) and positive p-RPS6 staining correlated with recurrence. RICTOR-specific siRNA down-regulation reduced tumor cell viability in vitro. Blockage of mTOR signaling with everolimus in vitro and in a xenograft model decelerated tumor growth and increased survival. This effect was enhanced in vivo after epidermal growth factor blockade. MTOR signaling has a critical role in the pathogenesis of HCC, with evidence for the role of RICTOR in hepato-oncogenesis. MTOR blockade with everolimus is effective in vivo. These findings establish a rationale for targeting the mTOR pathway in clinical trials in HCC.
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                Author and article information

                Journal
                OCL
                Oncology
                10.1159/issn.0030-2414
                Oncology
                S. Karger AG
                978-3-8055-9251-2
                978-3-8055-9252-9
                0030-2414
                1423-0232
                2010
                July 2010
                08 July 2010
                : 78
                : Suppl 1
                : 172-179
                Affiliations
                aDepartment of Microbiology and bGraduate Institute of Clinical Medicine, National Taiwan University and Hospital, College of Medicine, Taipei, Taiwan
                Article
                315247 Oncology 2010;78(suppl 1):172–179
                10.1159/000315247
                20616601
                f8d5ba42-1436-497b-96e4-db54ad6f487c
                © 2010 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                References: 84, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/315247
                Self URI (text/html): https://www.karger.com/Article/FullText/315247
                Self URI (journal page): https://www.karger.com/SubjectArea/Oncology
                Categories
                Paper

                Oncology & Radiotherapy,Pathology,Surgery,Obstetrics & Gynecology,Pharmacology & Pharmaceutical medicine,Hematology
                Hepatocellular carcinoma,Hepatitis B virus,Androgen receptor,Estrogen receptor,Androgen,Estrogen

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