Browsing by Subject "Carcinoma, Hepatocellular"

Now showing 1 - 7 of 7
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    Epithelial-mesenchymal transitions and hepatocarcinogenesis.
    (J Clin Invest, 2010-04) Jou, Janice; Diehl, Anna Mae
    Epithelial-mesenchymal transitions (EMTs) are believed to play a role in invasion and metastasis of many types of tumors. In this issue of the JCI, Chen et al. show that a gene that has been associated with aggressive biology in hepatocellular carcinomas initiates a molecular cascade that results in EMT.
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    Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.
    (PLoS One, 2011) Philips, GM; Chan, IS; Swiderska, M; Schroder, VT; Guy, C; Karaca, GF; Moylan, C; Venkatraman, T; Feuerlein, S; Syn, WK; Jung, Y; Witek, RP; Choi, S; Michelotti, GA; Rangwala, F; Merkle, E; Lascola, C; Diehl, AM
    OBJECTIVE: Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/-) mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC. METHODS: Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/-) mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. RESULTS: Unlike controls, Mdr2(-/-) mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. CONCLUSIONS: Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.
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    In vivo guidance and assessment of liver radio-frequency ablation with acoustic radiation force elastography.
    (Ultrasound Med Biol, 2008-10) Fahey, Brian J; Nelson, Rendon C; Hsu, Stephen J; Bradway, David P; Dumont, Douglas M; Trahey, Gregg E
    The initial results from clinical trials investigating the utility of acoustic radiation force impulse (ARFI) imaging for use with radio-frequency ablation (RFA) procedures in the liver are presented. To date, data have been collected from 6 RFA procedures in 5 unique patients. Large displacement contrast was observed in ARFI images of both pre-ablation malignancies (mean 7.5 dB, range 5.7-11.9 dB) and post-ablation thermal lesions (mean 6.2 dB, range 5.1-7.5 dB). In general, ARFI images provided superior boundary definition of structures relative to the use of conventional sonography alone. Although further investigations are required, initial results are encouraging and demonstrate the clinical promise of the ARFI method for use in many stages of RFA procedures.
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    In vivo visualization of abdominal malignancies with acoustic radiation force elastography.
    (Phys Med Biol, 2008-01-07) Fahey, BJ; Nelson, RC; Bradway, DP; Hsu, SJ; Dumont, DM; Trahey, GE
    The utility of acoustic radiation force impulse (ARFI) imaging for real-time visualization of abdominal malignancies was investigated. Nine patients presenting with suspicious masses in the liver (n = 7) or kidney (n = 2) underwent combined sonography/ARFI imaging. Images were acquired of a total of 12 tumors in the nine patients. In all cases, boundary definition in ARFI images was improved or equivalent to boundary definition in B-mode images. Displacement contrast in ARFI images was superior to echo contrast in B-mode images for each tumor. The mean contrast for suspected hepatocellular carcinomas (HCCs) in B-mode images was 2.9 dB (range: 1.5-4.2) versus 7.5 dB (range: 3.1-11.9) in ARFI images, with all HCCs appearing more compliant than regional cirrhotic liver parenchyma. The mean contrast for metastases in B-mode images was 3.1 dB (range: 1.2-5.2) versus 9.3 dB (range: 5.7-13.9) in ARFI images, with all masses appearing less compliant than regional non-cirrhotic liver parenchyma. ARFI image contrast (10.4 dB) was superior to B-mode contrast (0.9 dB) for a renal mass. To our knowledge, we present the first in vivo images of abdominal malignancies in humans acquired with the ARFI method or any other technique of imaging tissue elasticity.
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    Loss of tumor suppressor IGFBP4 drives epigenetic reprogramming in hepatic carcinogenesis.
    (Nucleic acids research, 2018-09) Lee, Ying-Ying; Mok, Myth Ts; Kang, Wei; Yang, Weiqin; Tang, Wenshu; Wu, Feng; Xu, Liangliang; Yan, Mingfei; Yu, Zhuo; Lee, Sau-Dan; Tong, Joanna HM; Cheung, Yue-Sun; Lai, Paul BS; Yu, Dae-Yeul; Wang, Qianben; Wong, Grace LH; Chan, Andrew M; Yip, Kevin Y; To, Ka-Fai; Cheng, Alfred SL
    Genomic sequencing of hepatocellular carcinoma (HCC) uncovers a paucity of actionable mutations, underscoring the necessity to exploit epigenetic vulnerabilities for therapeutics. In HCC, EZH2-mediated H3K27me3 represents a major oncogenic chromatin modification, but how it modulates the therapeutic vulnerability of signaling pathways remains unknown. Here, we show EZH2 acts antagonistically to AKT signaling in maintaining H3K27 methylome through epigenetic silencing of IGFBP4. ChIP-seq revealed enrichment of Ezh2/H3K27me3 at silenced loci in HBx-transgenic mouse-derived HCCs, including Igfbp4 whose down-regulation significantly correlated with EZH2 overexpression and poor survivals of HCC patients. Functional characterizations demonstrated potent growth- and invasion-suppressive functions of IGFBP4, which was associated with transcriptomic alterations leading to deregulation of multiple signaling pathways. Mechanistically, IGFBP4 stimulated AKT/EZH2 phosphorylation to abrogate H3K27me3-mediated silencing, forming a reciprocal feedback loop that suppressed core transcription factor networks (FOXA1/HNF1A/HNF4A/KLF9/NR1H4) for normal liver homeostasis. Consequently, the in vivo tumorigenicity of IGFBP4-silenced HCC cells was vulnerable to pharmacological inhibition of EZH2, but not AKT. Our study unveils chromatin regulation of a novel liver tumor suppressor IGFBP4, which constitutes an AKT-EZH2 reciprocal loop in driving H3K27me3-mediated epigenetic reprogramming. Defining the aberrant chromatin landscape of HCC sheds light into the mechanistic basis of effective EZH2-targeted inhibition.
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    Plasma miRNAs as early biomarkers for detecting hepatocellular carcinoma.
    (Int J Cancer, 2015-10-01) Wen, Yang; Han, Jing; Chen, Jianguo; Dong, Jing; Xia, Yongxiang; Liu, Jibin; Jiang, Yue; Dai, Juncheng; Lu, Jianhua; Jin, Guangfu; Han, Jiali; Wei, Qingyi; Shen, Hongbing; Sun, Beicheng; Hu, Zhibin
    The early detection of hepatocellular carcinoma (HCC) presents a challenge because of the lack of specific biomarkers. Serum/plasma microRNAs (miRNAs) can discriminate HCC patients from controls. We aimed to identify and evaluate HCC-associated plasma miRNAs originating from the liver as early biomarkers for detecting HCC. In this multicenter three-phase study, we first performed screening using both plasma (HCC before and after liver transplantation or liver hepatectomy) and tissue samples (HCC, para-carcinoma and cirrhotic tissues). Then, we evaluated the diagnostic potential of the miRNAs in two case-control studies (training and validation sets). Finally, we used two prospective cohorts to test the potential of the identified miRNAs for the early detection of HCC. During the screening phase, we identified ten miRNAs, eight of which (miR-20a-5p, miR-25-3p, miR-30a-5p, miR-92a-3p, miR-132-3p, miR-185-5p, miR-320a and miR-324-3p) were significantly overexpressed in the HBV-positive HCC patients compared with the HBV-positive cancer-free controls in both the training and validation sets, with a sensitivity of 0.866 and specificity of 0.646. Furthermore, we assessed the potential for early HCC detection of these eight newly identified miRNAs and three previously reported miRNAs (miR-192-5p, miR-21-5p and miR-375) in two prospective cohorts. Our meta-analysis revealed that four miRNAs (miR-20a-5p, miR-320a, miR-324-3p and miR-375) could be used as preclinical biomarkers (pmeta  < 0.05) for HCC. The expression profile of the eight-miRNA panel can be used to discriminate HCC patients from cancer-free controls, and the four-miRNA panel (alone or combined with AFP) could be a blood-based early detection biomarker for HCC screening.
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    Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma.
    (Lab Invest, 2010-12) Pereira, Tde A; Witek, RP; Syn, WK; Choi, SS; Bradrick, S; Karaca, GF; Agboola, KM; Jung, Y; Omenetti, A; Moylan, CA; Yang, L; Fernandez-Zapico, ME; Jhaveri, R; Shah, VH; Pereira, FE; Diehl, AM
    Hedgehog (Hh) pathway activation promotes many processes that occur during fibrogenic liver repair. Whether the Hh pathway modulates the outcomes of virally mediated liver injury has never been examined. Gene-profiling studies of human hepatocellular carcinomas (HCCs) demonstrate Hh pathway activation in HCCs related to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Because most HCCs develop in cirrhotic livers, we hypothesized that Hh pathway activation occurs during fibrogenic repair of liver damage due to chronic viral hepatitis, and that Hh-responsive cells mediate disease progression and hepatocarciongenesis in chronic viral hepatitis. Immunohistochemistry and qRT-PCR analysis were used to analyze Hh pathway activation and identify Hh-responsive cell types in liver biopsies from 45 patients with chronic HBV or HCV. Hh signaling was then manipulated in cultured liver cells to directly assess the impact of Hh activity in relevant cell types. We found increased hepatic expression of Hh ligands in all patients with chronic viral hepatitis, and demonstrated that infection with HCV stimulated cultured hepatocytes to produce Hh ligands. The major cell populations that expanded during cirrhosis and HCC (ie, liver myofibroblasts, activated endothelial cells, and progenitors expressing markers of tumor stem/initiating cells) were Hh responsive, and higher levels of Hh pathway activity associated with cirrhosis and HCC. Inhibiting pathway activity in Hh-responsive target cells reduced fibrogenesis, angiogenesis, and growth. In conclusion, HBV/HCV infection increases hepatocyte production of Hh ligands and expands the types of Hh-responsive cells that promote liver fibrosis and cancer.