Kirk Tran

 Introduction. Colorectal cancer (CRC) is the third most common cause of cancer-related mortalities worldwide¹. The pathogenesis of CRC is a multifactorial progression with accumulating genetic mutations and changes in expression levels of microRNAs². While studies have shown microRNA-21 (miR-21) to be upregulated in CRC, the exact molecular role of miR-21 in the post-transcriptional regulation of other pathways remains unclear^3,4. Other studies have elucidated its role by showing that miR-21 interacts with PDCD4, a tumor suppressor gene, and COX-2, a key enzyme in inflammation, in the progression of CRC^1,4,5. These findings could suggest microRNA-21 and COX-2 inhibitors as potential therapy for CRC.  Methods. Multiple models were utilized to evaluate the functional interaction between microRNA-21, PDCD4, and COX-2. In cell-based experiments, human colorectal adenocarcinoma cell lines were utilized to analyze relative protein expression levels and metastatic potential^1,4,5. Tumor formation was evaluated in a colitis-associated cancer model induced by azoxymethane (AOM) and dextran sulfate sodium (DSS) treatment of miR-21 knockout (mir-21 flox/flox) and wild type mice in the C57BL/6 background³. Clinical samples were obtained from patients with CRC treated with microRNA-21 inhibitors, COX-2 inhibitor NS398, or PGE2 to evaluate message and protein levels of relevant targets of interest^1,4,5. Results. A functional interaction was demonstrated between miR-21, COX-2, and PDCD4. Cells transfected with a miR-21 inhibitor showed no significant changes in PDCD4 mRNA levels (p=0.5) but did show significant increase in PDCD4 protein levels (p=0.002). These results indicate miR-21 acts to inhibit PDCD4 mRNA at the post-transcriptional level. Cells treated with the COX-2 inhibitor NS398 (p<0.01) or PGE2 showed increased miR-21 expression (p=0.019), indicating miR-21 as a downstream target of the COX-2 mediated inflammatory pathway¹. A study showed miR-21 KO mice with decreased number and size of visible tumors (p<0.05). The miR-21 KO mice also produced significantly less proinflammatory molecules (TNF-a, IL-6, COX-2) in the colon (p<0.05). Wild type mice showed decreased PDCD4 protein levels (p<0.001)⁴. Another study demonstrated CRC cells transfected with locked nucleic acid-anti-miR-21 showed reduced PDCD4 mRNA levels (p<0.01), cell migration (p<0.01), and cluster formation (p<0.01)⁵. Conclusions. These studies illustrated the regulatory interaction between miR-21 and other pathways in the pathogenesis of colorectal cancer. Increased COX-2 during inflammatory conditions upregulates the expression of miR-21, which then represses PDCD4 in facilitating invasion and metastasis of CRC. These findings demonstrate the therapeutic potential of combined use of anti-inflammatory drugs with miR-21 inhibitors in CRC.

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3. Thomas J, Ohtsuka M, Pichler M, Ling H. MicroRNAs: Clinical relevance in colorectal cancer. International Journal of Molecular Sciences. 2015;16(12):28063-28076.
4. Shi C, Yang Y, Xia Y, et al. Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer. Gut. 2016;65(9):1470-1481. http://gut.bmj.com/content/65/9/1470.abstract. doi: 10.1136/gutjnl-2014-308455.
5. Nedaeinia R, Sharifi M, Avan A, et al. Inhibition of microRNA-21 via locked nucleic acid-anti-miR suppressed metastatic features of colorectal cancer cells through modulation of programmed cell death 4. Tumour Biol. 2017;39(3):1010428317692261.