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Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
Epigenetic regulation of microRNA expression in colorectal cancer
Eva Bandres1, Xabier Agirre, Nerea Bitarte
1Division of Oncology, Laboratory of Pharmacogenomics, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain. ebandres@unav.es
Abstract:
In the last years, microRNAs (miRNA) have emerged as new molecular players involved in carcinogenesis. Deregulation of miRNAs expression has been shown in different human cancer but the molecular mechanism underlying the alteration of miRNA expression is unknown. To identify tumor-supressor miRNAs silenced through aberrant epigenetic events in colorectal cancer (CRC), we used a sequential approach. We first identified 5 miRNAs down-regulated in patient with colorectal cancer samples and located around/on a CpG island. Treatment with a DNA methyltransferase inhibitor and a HDAC inhibitor restored expression of 3 of the 5 microRNAs (hsa-miR-9, hsa-miR-129 and hsa-miR-137) in 3 CRC cell lines. Expression of hsa-miR-9 was inversely correlated with methylation of their promoter regions as measure by MSP and bisulphate sequencing. Further, methylation of the hsa-miR-9-1, hsa-miR-129-2 and hsa-miR-137 CpG islands were frequently observed in CRC cell lines and in primary CRC tumors, but not in normal colonic mucosa. Finally, methylation of hsa-miR-9-1 was associated with the presence of lymph node metastasis. In summary, our results aid in the understanding of miRNA gene regulation showing that aberrant DNA methylation and histone modifications work together to induce silencing of miRNAs in CRC.
Insights
Aberrant DNA methylation and histone changes silence tumor-suppressor microRNAs (miRNAs) in colorectal cancer (CRC). This epigenetic silencing, particularly of hsa-miR-9, is frequent in CRC tumors and linked to metastasis.
Area of Science:
- Epigenetics
- Molecular Biology
- Oncology
Background:
- MicroRNAs (miRNAs) are implicated in cancer development.
- The mechanisms causing miRNA deregulation in colorectal cancer (CRC) are not fully understood.
Purpose of the Study:
- To identify tumor-suppressor miRNAs silenced by epigenetic alterations in CRC.
- To investigate the role of DNA methylation and histone modifications in miRNA gene silencing in CRC.
Main Methods:
- Identified down-regulated miRNAs in CRC patients' samples located near CpG islands.
- Used DNA methyltransferase and HDAC inhibitors to restore miRNA expression in CRC cell lines.
- Analyzed promoter methylation using methylation-specific PCR (MSP) and bisulfite sequencing.
- Correlated miRNA methylation with clinical parameters like lymph node metastasis.
Main Results:
- Five miRNAs were found to be down-regulated in CRC.
- Treatment with epigenetic inhibitors restored expression of hsa-miR-9, hsa-miR-129, and hsa-miR-137.
- Promoter methylation of these miRNAs was frequent in CRC cell lines and tumors, but not normal tissue.
- hsa-miR-9 promoter methylation correlated inversely with its expression.
- Methylation of hsa-miR-9-1 was associated with lymph node metastasis in CRC patients.
Conclusions:
- Aberrant DNA methylation and histone modifications cooperate to silence tumor-suppressor miRNAs in colorectal cancer.
- Epigenetic silencing of miRNAs like hsa-miR-9 contributes to CRC progression and metastasis.
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