Expression of miR-34 is lost in colon cancer which can be re-expressed by a novel agent CDF

Background: Colorectal Cancer (CRC) is one of the leading causes of death worldwide. Numerous cellularevents, including deregulated expression of microRNAs (miRNAs), specifically the family ofmiR-34 consisting of miR-34a, b and c, which is known to regulate the processes of growthand metastasis. Methods: We evaluated the expression of miR-34 in formalin-fixed paraffin-embedded (FFPE) humancolon cancer tissue specimens compared to normal colonic mucosa. Moreover, we alsoassessed the expression of miR-34 in colon cancer cell lines treated with our newly developedsynthetic analogue of curcumin referred as diflurinated curcumin (CDF) compared to wellknown inhibitor of methyl transferase. Results: We found that the expression of miR-34a and miR-34c was down-regulated in colon cancerspecimens compared to normal colonic mucosa and the loss of expression was also consistentwith data from colon cancer cell lines. This down-regulation was attributed to promoterhypermethylation, because we found that the treatment of colon cancer cells with 5-aza-2'-deoxycytidine, a methyltransferase inhibitor, markedly induced the levels of miR-34a andmiR-34c expression. Likewise, CDF was very effective in the re-expression of miR-34a andmiR-34c, which was consistent with inhibition of cell growth of both chemo-sensitive andchemo-resistant colon cancer cells. The re-expression of miR-34 led to a marked reduction inthe expression of its target gene, Notch-1. Conclusion: The loss of expression of miR-34 in colon cancer is in part due to promoter hypermethylationof miR-34, which can be re-expressed with our novel agent CDF, suggesting that CDF couldbe a novel demethylating agent for restoring the expression of miR-34 family, and thus CDFcould become a newer therapeutic agent for the treatment of colon cancer.

via Journal of Hematology & Oncology