Abstract
Deregulation of imprinted genes is an important molecular mechanism contributing to the development of cancer in humans. However, knowledge about imprinting defects in human hepatocellular carcinoma (HCC), the third leading cause of cancer mortality worldwide, is still limited. Therefore, a systematic meta-analysis of the expression of 223 imprinted loci in human HCC was initiated. This screen revealed that the DLK1-MEG3 locus is frequently deregulated in HCC. Deregulation of DLK1 and MEG3 expression accompanied by extensive aberrations in DNA methylation could be confirmed experimentally in an independent series of human HCC (n = 40) in more than 80% of cases. Loss of methylation at the DLK1-MEG3 locus correlates linearly with global loss of DNA methylation in HCC (r2 = 0.63, p<0.0001). Inhibition of DNMT1 in HCC cells using siRNA led to a reduction in MEG3-DMR methylation and concomitant increase in MEG3 RNA expression. Allele-specific expression analysis identified loss of imprinting in 10 out of 31 informative samples (32%), rendering it one of the most frequent molecular defects in human HCC. In 2 cases unequivocal gain of bi-allelic expression accompanied by substantial loss of methylation at the IG-DMR could be demonstrated. In 8 cases the tumour cells displayed allelic switching by mono-allelic expression of the normally imprinted allele. Allelic switching was accompanied by gains or losses of DNA methylation primarily at IG-DMR1. Analysis of 10 hepatocellular adenomas (HCA) and 5 cases of focal nodular hyperplasia (FNH) confirmed that this epigenetic instability is specifically associated with the process of malignant transformation and not linked to increased proliferation per se. This widespread imprint instability in human HCC has to be considered in order to minimize unwanted side-effects of therapeutic approaches targeting the DNA methylation machinery. It might also serve in the future as predictive biomarker and for monitoring response to epigenetic therapy.
Highlights
The development of cancer in humans is caused by genetic lesions [1], and by epigenetic aberrations [2]
Subsequent analyses focussed on the non-coding RNA MEG3, because it showed the most frequent deregulation of expression in primary hepatocellular carcinoma (HCC) according to this meta-analysis and in an initial screen performed by ourselves
Despite the fact that a relationship between imprinting defects and the development of cancer in humans is known for more than 20 years [35] this is still an underdeveloped area of research in comparison to e.g., the role of mutated oncogenes in human tumours. This is especially true for human HCC, the third leading cause of cancer mortality worldwide
Summary
The development of cancer in humans is caused by genetic lesions (mutations, deletions, translocations etc.) [1], and by epigenetic aberrations [2]. One epigenetic phenomenon whose deregulation contributes to the development and progression of cancer in humans is imprinting, the parent-of-origin specific expression of genes. Contribution of imprinting defects in cancer is best exemplified in patients with Beckwith-Wiedemann syndrome (BWS) [6,7]. Deregulation of imprinted genes in the 11p15.5 imprinting locus caused by mutations, epimutations, or uniparental inheritance affects proliferation control in BWS patients predisposing them with a 600 fold increase in cancer risk, especially for embryonic tumours such as Wilms’ tumour or hepatoblastoma [8]
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