MicroRNA-Mediated Migration of Colon Cancer Cells

Abstract: Colorectal cancer (CRC) is the second most common cancer in women and third most common cancer in men worldwide. The cause of the majority of death related to CRC is believed to be the migration of cancer cells to distant organs which is known as cancer metastasis. The mechanism behind cancer cell metastasis is not fully understood but accumulating studies suggest that it could be due to enhanced tumor cell motility due to overexpression of metastasis related proteins. It is believed that microRNAs (miRNAs) play a significant role in the tumorigenesis and metastasis of cancer by regulating oncogenes. The aim of this thesis is to investigate the mechanism of miRNA-mediated colon cancer cell invasion and migration as well as possible targets genes of miRNAs. We found that knockdown of miR-155-5p by antagomiR reduces the expression of HuR mRNA and migration of colon cancer cells. Our data also showed that miR-155-5p is involved in positive regulation of HuR protein under stress conditions. Notably, this positive regulation is regulated by direct binding of miR-155-5p at AU rich element region in 3ʹ-UTR of HuR mRNA. In addition, it was found that miR-340-5p is also involved in colon cancer cell invasion and migration by regulating RhoA and FHL2 mRNA expression. Bioinformatics analysis revealed that both RhoA and FHL2 mature mRNA have conserved binding sites from 2 to 8 base positions for miR-340-5p. The seed region of miR-340-5p directly binds with the target sites of RhoA and FHL2 mRNA and negatively regulate their expression under stress conditions. We found that the inhibition of RhoA and FHL2 expression by the use of mimic miR-340-5p reduced colon cancer cells invasion and migration. In addition, it was found that inhibition of FHL2 reduces cancer cells proliferation and increases E-cadherin expression in colon cancer cells, suggesting that targeting FHL2 and RhoA by miR-340-5p might be a useful approach to antagonize colon cancer cells metastasis. The results of our studies not only show diverse mechanisms of colon cancer cells migration, but also provided valuable information that miRNAs can be an important target to develop new and effective therapeutics against colon cancer cells metastasis. Taken together, our data uncovered several new mechanisms for better understanding the mechanism of colon cancer cells metastasis and suggest that targeting miRNAs function could be a useful strategy to prevent colon cancer metastasis.