[Frontiers in Bioscience, Landmark, 20, 946-963, June 1, 2015]

Epigenetic regulation of hepatic tumor-initiating cells

Jia Ding 1, 2 , Jian Wu 1, 3, 4

1Key Laboratory of Medical Molecular Virology, Ministries of Education and Public Health, Fudan University Shanghai Medical College, Shanghai 200032, China; 2Department of Gastroenterology, Shanghai Jing’an District Central Hospital, Shanghai 200040, China; 3University of California, Davis Medical Center, Dept. of Internal Medicine, Division of Gastroenterology & Hepatology, Sacramento, CA 95817, USA; 4Shanghai Institute of Liver Diseases, Fudan University Affiliated Zhongshan Hospital, Shanghai 200032, China


1. Abstract
2. Introduction
3. Common epigenetic regulations of hepatocellular carcinoma (HCC)
    3.1. Histone modifications
    3.2. DNA methylation
4. Liver stem cells and putative hepatic tumor-initiating cells
    4.1. Normal liver progenitor cells and surface markers
    4.2. Definition of tumor-initiating cells (T-ICs) or cancer stem cells (CSCs)
    4.3. Side subpopulation
5. Role of etiology and microenvironmental changes in epigenetic modifications
    5.1. Hepatitis B viral infection
    5.2. Hepatitis C viral infection
    5.3. Chronic inflammation
    5.4. Oxidative stress
6. Epigenetic modification facilitates the transformation towards T-ICs
    6.1. Histone ubiquitination and acetylation
    6.2. DNA methylation and demethylation
    6.3. Epigenetic modification of transcription factors affecting pluripotency
    6.4. Aberrant hedgehog signaling in hepatic T-ICs
    6.5. Abnormal activation of Wnt-beta-catenin signaling activity
7. Role of microRNAs in modulating epigenetic status
    7.1. miR-148a
    7.2. miR-122
    7.3. miR-214
8. Epithelial mesenchymal transition in epigenetic aberrations
9. Conclusions and perspectives
10. Acknowledgements
11. References


Hepatocellular carcinoma (HCC) is the third most lethal cancer and resistant to common chemotherapy. Tumor-initiating cells (T-ICs) that are thought to be responsible for tumorigenesis share surface markers and signaling pathways similar to normal tissue stem cells. Identification of T-ICs and elucidation of aberrant epigenetic modulation and self-renewal pathways may provide new insights into hepatic carcinogenesis, metastasis and chemotherapeutic resistance. Histone modification, DNA methylation and microenvironmental changes are considered as key elements to promote the derivation and function of T-ICs. In this review, we intend to compare the similarity and difference between normal liver stem cells and T-ICs, and to define the intrinsic and micro-environmental factors that lead to the transformation from normal liver stem cells to hepatic T-ICs. We believe that etiology, microenvironmental alteration, epigenetic modification and epithelial-mesenchymal transition play a fundamental role in initiating the transformation. Strategies targeting signaling molecules critical in modulating these processes may offer a personalized therapy for HCC in the future.


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Abbreviations: ABC, adenosine triphosphate (ATP)-binding cassette, ALDH-1, aldehyde dehydrogenase-1, Bmi-1, B lymphoma moloney murine leukemia virus insertion region 1 homolog, ChIP, chromatin immunoprecipitation, CpG, cytosine-guanine dinucleotide, CRBP-1, cellular retinol-binding protein-1, CSCs, cancer stem cells, DNMT, DNA methyltransferase, EMT, epithelial-mesenchymal transition, EpCAM, epithelial cell adhesion molecule, ERK, extracellular signal-regulated kinase, EZH2, enhancer of zeste homolog-2, HAT, histone acetyltransferase, HBx, hepatitis B viral X protein, HCC, hepatocellular carcinoma, HDAC, histone deacetylase, HDM, histone demethylase, HGF, hepatocyte growth factor, HMT, histone methyltransferase, hTERT, human telomerase reverse transcriptase, ICAM-1, intercellular cell adhesion molecule-1, iPSC, induced pluripotent stem cells, LINE-1, long interspersed nucleotide element-1, LPC, liver progenitor cells, MDR-1, multidrug resistance gene-1, NAFLD, non-alcoholic fatty liver disease, NCAM, neural cell adhesion molecule, OV-6, oval cell marker-6, PGP, polycomb group protein, PPAR-gamma, peroxisome proliferator activated receptor-gamma, PRC, polycomb repressive complex, PTEN, phosphatase and tensin homolog deleted on chromosome-10, RBP, retinol-binding protein precursor, ROS, reactive oxygen species, RXR-alpha, retinoid X receptor-alpha, SFRP, secreted frizzled related protein, SP, side population, TGF-beta, transforming growth factor-beta, T-ICs, tumor-initiating cells, TSG, tumor suppressor gene, UTR, untranslated region

Key Words: Tumor-initiating cells; Cancer stem cells; Epigenetic regulation; Hepatocellular carcinoma, Review

Send correspondence to: Jian Wu, Key Laboratory of Medical Molecular Virology, Fudan University Shanghai Medical College, 138 Yi Xue Yuan Road, Shanghai 200032, China, Tel: 86-21-5423-7705, Fax: 86-21-6422-7201, E-mail: jdwu@ucdavis.edu