Epigenetic regulation of microRNA expression in colorectal cancer

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. ' 2009 UICC

Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma

“…Previous studies have shown extensive epigenetic silencing of one or several of the miR-9 genes in cancer (Lehmann et al, 2008;Lujambio et al, 2008;Omura et al, 2008;Bandres et al, 2009;Hsu et al, 2009). This silencing was common in tumor tissue, whereas nearly absent in normal tissue.…”

“…However, the differences between the methylation statuses of miR-9-1 and miR-9-3 are clearly evident utilizing these specimens. Hypermethylation of the two hsa-miR-9 genes has been shown to be even more evident in tumors with lymph node metastases in colon, lung, breast and melanoma cancers (Lujambio et al, 2008;Bandres et al, 2009). In our ccRCC tumor samples, this was also observed with patients developing a recurrence having a higher occurrence of methylated miR-9-1 and miR-9-3 in their primary tumor compared with those who have not at time of analysis (Figure 2).…”

“…Furthermore, studies of liver (Budhu et al, 2008), breast (Iorio et al, 2005) and colorectal (Bandres et al, 2009) cancers have shown that altered hsa-miR-9 expression was associated with metastatic tumors. Our findings are that both miR-9-1 and miR-9-3 are hypermethylated, and thus silenced in tumor compared with adjacent normal, and also in the primary tumors of those who developed recurrences compared with those who did not are in agreement with the published expression data.…”

“…The mature hsa-miR-9 transcript is produced by three independent genes: miR-9-1, miR-9-2 and miR-9-3, located on chromosomes 1, 5 and 15, respectively. Previous studies have shown that these microRNA genes are commonly hypermethylated in tumor tissue (Lehmann et al, 2008;Lujambio et al, 2008;Omura et al, 2008;Bandres et al, 2009;Hsu et al, 2009). Furthermore, hsa-miR-9 methylation was shown to be associated with the development of metastasis (Lujambio et al, 2008;Bandres et al, 2009).…”

The Colorectal Tumor Microenvironment: The Next Decade

“…Yet, the enormous research efforts of the last decade promise major discoveries and novel implementation relative to potential treatments for CRC that will hopefully be available within the next 10 years. New findings implicating mutations in metastasis suppressor genes [1] or in known oncogenic pathways such as KRAS, BRAF, PTEN, IGFR1 and EGFR [2-4] as well as epigenetic alterations involving DNA methylation dysregulation and/or chromatin remodeling [5] and miRNA control of gene expression [6] have greatly expanded the knowledge of how metastatic dissemination proceeds. The constant interplay between the tumor and its surrounding microenvironment continuously modifies their synergistic mechanisms and responses generally to the tumor's advantage, such that attacking the lesions on all fronts becomes a necessity.…”