ABSTRACT
Overview ................................................................................................................ 142 7.1 Hepatocellular Carcinoma ............................................................................ 143 7.2 Folate Deˆciency .......................................................................................... 144
7.2.1 Rodent Models of Folate Deˆciency and Hepatocellular Carcinoma ......................................................................................... 145
7.2.2 Epigenetic Alterations in Rodent Models of Diet-Induced HCC ..... 147 7.3 Introduction to MicroRNA ........................................................................... 154
7.3.1 MicroRNA Genes and Biogenesis of MicroRNAs ........................... 155 7.3.2 Function of MicroRNAs ................................................................... 156 7.3.3 MicroRNAs Expressed in the Liver ................................................. 157
7.4 Aberrations in MicroRNA Expression Occur in Hepatocellular Carcinomas ................................................................................................... 157 7.4.1 MicroRNAs Dysregulated in the Rat Model of Folate Methyl-
Deˆcient (FMD) Diet-Induced HCC ................................................ 157 7.4.2 MicroRNAs Dysregulated in the Mouse Model of NASH-
Induced Hepatocarcinogenesis Developed by Feeding CDAA Diet ................................................................................... 162
7.4.3 MicroRNA Alteration in Human HCC............................................. 164 7.4.4 Hepatic MicroRNAs Dysregulated in NASH Patients ..................... 165
7.5 MicroRNAs with Important Function in Liver and HCC ............................ 166 7.5.1 miR-122 ............................................................................................ 166 7.5.2 miR-181 ............................................................................................. 167 7.5.3 miR-155 ............................................................................................. 168
7.6 Epigenetic Regulation of MicroRNA Expression in Hepatocellular Cancer ........................................................................................................... 168
7.7 Concluding Remarks .................................................................................... 169 Acknowledgment ................................................................................................... 170 References .............................................................................................................. 170
It is now well established that cancer is both a genetic and epigenetic disease. Although existence of DNA methylation and histone modiˆcations in biological systems was known for decades, only studies in the last 15 years have recognized that these postreplication modiˆcations play key roles in epigenetic regulation of gene expression (Figure 7.1). Emerging studies now support the notion that noncoding RNAs will be major players in the regulation of expression of coding regions by affecting chromatin structure, transcription, mRNA stability, and translation, thereby adding to the ensemble of epigenetic “equipment.” Indeed, a surprising revelation of the postgenomic era is that only a miniscule amount of the mammalian genome (<5%) codes for proteins, while the major part of the once thought to be “junk DNA” codes for noncoding RNAs ranging in size from a few nucleotides to
FIGURE 7.1 Schematic representation of Dnmts and MBDs involved in epigenetic silencing of genes. A. Three functional Dnmts are highly conserved in mammals. Simpliˆed mechanism of methylation mediated silencing. B. Schematic diagram of MBD family members. MBD and TRD stand for methyl CpG binding domain and transcriptional repressor domain, respectively. C. Schematic representation of methylation-mediated silencing of genes. Nucleosomes wrapped around transcriptionally active promoters are relaxed, with CpG base pairs unmethylated and core nucleosomal histones acetylated. Dnmt3a or Dnmt3b (de novo methyl transferase) initiate methylation of CpG base pairs, which are maintained postreplication by Dnmt1. Methyl CpG binding proteins then bind to the methylated CpGs and recruit different corepressors, resulting in nucleosomal condensation and epigenetic silencing. Open and ˆlled lollipops denote methylated and unmethylated CpG, respectively. MBD and TRD stand for methyl CpG binding domain and transcriptional repressor domain, respectively. (Modiˆed from Ghoshal, K., Li, X., Datta, J., et al., J Nutr, 136, 1522-27, 2006. With permission.)
several hundred kb (Figure 7.2). Among these, microRNAs (miRs) are small (21-25 nt) noncoding RNAs that negatively regulate expression of protein-coding genes primarily at the posttranscriptional level in animals. These tiny RNAs are essential for animal development, and aberrations in their expression lead to different diseased states such as cancer, viral infection, in•ammation, diabetes, and cardiovascular neuronal disorders. Recent studies have shown that in addition to genetic factors and lifestyle, diet plays a major causal role in metabolic syndromes that increase the risk of several diseases including cardiovascular disorders, diabetes, and cancer in humans. MicroRNAs have tremendous therapeutic potential since they are involved in every aspect of biology including metabolic disorders that often lead to liver cancer. In this chapter, we discuss how dietary manipulations modulate epigenetic machinery and the expression of cancer-causing protein-coding and noncoding (microRNA) genes during multistage hepatocarcinogenesis in animal models. We also discuss how epigenetic mechanisms modulate microRNA expression in hepatocellular cancer. Finally, we conclude with the potential of epigenetic and microRNA therapy against this disease with increasing mortality.
