Department of Veterans Affairs Medical Center, Wayne State University, Detroit, MI 48201, USA.
J Hematol Oncol. 2012 Sep 19;5:58. doi: 10.1186/1756-8722-5-58.
Colorectal Cancer (CRC) is one of the leading causes of death worldwide. Numerous cellular events, including deregulated expression of microRNAs (miRNAs), specifically the family of miR-34 consisting of miR-34a, b and c, is known to regulate the processes of growth and metastasis.
We evaluated the expression of miR-34 in formalin-fixed paraffin-embedded (FFPE) human colon cancer tissue specimens compared to normal colonic mucosa. Moreover, we also assessed the expression of miR-34 in colon cancer cell lines treated with our newly developed synthetic analogue of curcumin referred as difluorinated curcumin (CDF) compared to well known inhibitor of methyl transferase.
We found that the expression of miR-34a and miR-34c was down-regulated in colon cancer specimens compared to normal colonic mucosa and the loss of expression was also consistent with data from colon cancer cell lines. This down-regulation was attributed to promoter hypermethylation, 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 and miR-34c expression. Likewise, CDF was very effective in the re-expression of miR-34a and miR-34c, which was consistent with inhibition of cell growth of both chemo-sensitive and chemo-resistant colon cancer cells. The re-expression of miR-34 led to a marked reduction in the expression of its target gene, Notch-1.
The loss of expression of miR-34 in colon cancer is in part due to promoter hypermethylation of miR-34, which can be re-expressed with our novel agent CDF, suggesting that CDF could be a novel demethylating agent for restoring the expression of miR-34 family, and thus CDF could become a newer therapeutic agent for the treatment of colon cancer.
结直肠癌（CRC）是全球主要死因之一。许多细胞事件，包括微 RNA（miRNA）的表达失调，特别是 miR-34 家族，由 miR-34a、b 和 c 组成，被认为可以调节生长和转移过程。
我们评估了 miR-34 在福尔马林固定石蜡包埋（FFPE）的人类结肠癌组织标本与正常结肠黏膜中的表达。此外，我们还评估了在我们新开发的姜黄素合成类似物二氟化姜黄素（CDF）处理的结肠癌细胞系中的 miR-34 的表达，与甲基转移酶抑制剂进行比较。
我们发现，与正常结肠黏膜相比，miR-34a 和 miR-34c 在结肠癌标本中的表达下调，而且表达缺失也与结肠癌细胞系的数据一致。这种下调归因于启动子超甲基化，因为我们发现，甲基转移酶抑制剂 5-氮杂-2´-脱氧胞苷处理结肠癌细胞，显著诱导 miR-34a 和 miR-34c 的表达水平。同样，CDF 非常有效地重新表达 miR-34a 和 miR-34c，这与抑制化疗敏感和化疗耐药的结肠癌细胞的生长一致。miR-34 的重新表达导致其靶基因 Notch-1 的表达明显减少。
结肠癌中 miR-34 的表达缺失部分归因于 miR-34 的启动子超甲基化，这可以用我们的新型药物 CDF 重新表达，这表明 CDF 可能是一种新型的去甲基化药物，可以恢复 miR-34 家族的表达，因此 CDF 可能成为治疗结肠癌的新治疗剂。
