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Detection of a Circulating MicroRNA Custom Panel in Patients with Metastatic Colorectal Cancer
Published on: March 14, 2019
Expression of miR-34 is lost in colon cancer which can be re-expressed by a novel agent CDF
Sanchita Roy1, Edi Levi, Adhip P N Majumdar
1Department of Veterans Affairs Medical Center, Wayne State University, Detroit, MI 48201, USA.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Colorectal cancer (CRC) involves miR-34 down-regulation due to promoter hypermethylation. A novel curcumin derivative, CDF, effectively re-expresses miR-34 and inhibits CRC cell growth, suggesting therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Colorectal cancer (CRC) is a major global health concern.
- MicroRNAs (miRNAs), particularly the miR-34 family (miR-34a, b, c), play a role in regulating cell growth and metastasis in CRC.
- Deregulated miRNA expression is a known factor in cancer development.
Purpose of the Study:
- To investigate the expression levels of miR-34 in colorectal cancer tissues and cell lines.
- To explore the potential of a novel synthetic curcumin analogue, difluorinated curcumin (CDF), in restoring miR-34 expression.
- To evaluate CDF's effect on colon cancer cell growth and its underlying molecular mechanisms.
Main Methods:
- Comparative analysis of miR-34 expression in human colon cancer tissues versus normal colonic mucosa.
- Assessment of miR-34 expression in colon cancer cell lines treated with CDF and a methyltransferase inhibitor (5-aza-2´-deoxycytidine).
- Evaluation of cell growth inhibition in response to CDF treatment in chemo-sensitive and chemo-resistant colon cancer cells.
- Analysis of Notch-1 expression, a target gene of miR-34.
Main Results:
- miR-34a and miR-34c expression were significantly down-regulated in colon cancer specimens and cell lines compared to normal tissues.
- Promoter hypermethylation was identified as a key mechanism contributing to miR-34 down-regulation.
- Treatment with 5-aza-2´-deoxycytidine and CDF markedly induced miR-34a and miR-34c expression.
- CDF treatment inhibited the growth of both chemo-sensitive and chemo-resistant colon cancer cells.
- Re-expression of miR-34 led to a reduction in the expression of its target gene, Notch-1.
Conclusions:
- Loss of miR-34 expression in colon cancer is partly attributed to promoter hypermethylation.
- The novel agent CDF effectively re-expresses miR-34 family members, suggesting it acts as a demethylating agent.
- CDF demonstrates potential as a therapeutic agent for colon cancer by restoring miR-34 expression and inhibiting tumor growth.
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