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Genome-wide Screen for miRNA Targets Using the MISSION Target ID Library
Published on: April 6, 2012
Downregulation of the microRNA biogenesis components and its association with poor prognosis in hepatocellular
Noriyuki Kitagawa1, Hidenori Ojima, Takuya Shirakihara
1Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
Abstract:
Genetic alterations and deregulation of the miRNA biogenesis pathway components have been reported in human tumors. Tissue-specific deletion of the Dicer gene, which encodes an essential miRNA processing enzyme, promotes carcinogenesis in animal models. These features indicate that aberrant miRNA biogenesis components are directly associated with cancer. For the present study, we conducted quantitative RT-PCR of 14 genes that are related to the miRNA biogenesis pathway in 47 paired samples of primary hepatocellular carcinoma (HCC) and matched non-cancerous liver. Expression of seven genes (Dgcr8, p68, p72, Dicer, Ago3, Ago4 and Piwil4) was significantly decreased in primary HCC, especially in non-viral HCC subtypes, compared to the non-cancerous liver. Combinations of decreased expression of the miRNA biogenesis components in non-cancerous liver were related to cigarette smoking, alcohol intake and diabetes, which are known to be risk factors for HCC, and were also associated with the occurrence of multicentric tumors. Reduction of two of these genes (Dicer and p68) in HCC was associated with poor prognosis. Trimethylation of histone H3 lysine 27 in the promoters is implicated in the deregulation of these miRNA-biogenesis-related genes in non-HBV genome integrated HCC cell lines. In conclusion, deregulation of the miRNA biogenesis pathway components is frequently observed in non-viral-associated HCC and is linked to etiological risk factors and poor prognosis. Our study further showed that epigenetic regulation could be implicated in the deregulation of these genes during hepatocarcinogenesis.
Insights
Deregulation of microRNA (miRNA) biogenesis genes is common in non-viral hepatocellular carcinoma (HCC). Reduced expression of these genes correlates with risk factors, multicentric tumors, and poor HCC prognosis, suggesting epigenetic links.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Genetic alterations in miRNA biogenesis are implicated in human cancers.
- Dicer gene deletion promotes carcinogenesis in animal models, highlighting miRNA's role in cancer.
- Aberrant miRNA biogenesis components are linked to cancer development.
Purpose of the Study:
- To investigate the expression of miRNA biogenesis pathway genes in hepatocellular carcinoma (HCC).
- To correlate gene expression with HCC subtypes, risk factors, tumor characteristics, and patient prognosis.
- To explore the role of epigenetic regulation in miRNA biogenesis gene deregulation in HCC.
Main Methods:
- Quantitative RT-PCR was used to analyze the expression of 14 miRNA biogenesis genes.
- 47 paired samples of primary HCC and matched non-cancerous liver tissue were analyzed.
- Histone modification analysis (H3K27 trimethylation) was performed on HCC cell lines.
Main Results:
- Seven miRNA biogenesis genes showed decreased expression in HCC, particularly in non-viral HCC.
- Reduced expression correlated with risk factors (smoking, alcohol, diabetes), multicentric tumors, and poor prognosis (Dicer, p68).
- Epigenetic regulation via histone H3 lysine 27 trimethylation was implicated in gene deregulation in non-HBV HCC cell lines.
Conclusions:
- Deregulation of miRNA biogenesis pathway components is frequent in non-viral HCC.
- This deregulation is associated with etiological risk factors and predicts a poor prognosis.
- Epigenetic mechanisms, such as histone modifications, contribute to miRNA biogenesis gene deregulation during hepatocarcinogenesis.
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