Reduced Expression of MicroRNA‐200 Family Members Lead to Epithelial‐Mesenchymal Transition of a Chemoresistant Colorectal Cancer Cell Line

Abstract

After a patient's tumor is removed, he/she undergoes adjuvant chemotherapy and/or radiotherapy. Both of these treatments lead to formation of resistant cells that become metastatic cancer cells. The cellular program responsible for the change of epithelial tumors (such as breast, colorectal, pancreatic, and ovarian) into metastatic mesenchymal cell types is Epithelial‐Mesenchymal Transition (EMT). EMT is a normal process during embryogenesis, where epithelial cells lose their characteristics and become motile mesenchymal cells. Invasive and metastatic characteristics of carcinoma cells in primary tumors are mediated by EMT. During EMT, the primary tumor cells lose cell‐cell adhesion, normally mediated by E‐cadherin, and attain mesenchymal markers. The cells exhibit increased intercellular separation and elongated shape with pseudopodia. We developed a chemoresistant colorectal cancer cell line (DLD‐1 OxR) by exposing DLD‐1 colorectal cancer cells to increasing concentrations of oxaliplatin (a chemotherapy drug used for colorectal cancer). DLD‐1 OxR cells exhibit increased intercellular separation, increased motility, and elongated spindle shape with pseudopodia. MicroRNAs (miRNAs) are small non‐coding RNAs that regulate gene expression postranscriptionally. MiRNA, with silencing complexes, bind 3′ untranslated regions which lead to degradation of RNA or translation repression. Recent studies show that miRNA‐200 family members regulate the EMT process and metastasis. Decreased expression of miRNA‐200 family members leads to metastatic transformation of cancer cells. One of the miRNA‐200 family members is miRNA‐200c. Our hypothesis is that miRNA‐200c expression is decreased in DLD‐1 OxR cells. Loss of miRNA‐200c leads to expression of several regulatory genes involved in EMT, such as, Suz12 (one of the polycomb repressive complex proteins) and claudin‐1 (an integral membrane protein). We have found that miRNA‐200c expression is lower in DLD‐1 OxR cells compared to the parental DLD‐1 cells. Also, the miRNA‐200c targets are upregulated in DLD‐1 OxR. In conclusion, our study suggests that miRNA‐200c is involved in the EMT process in colorectal cancer cells.Support or Funding InformationKS and AM are supported by the DeNardo Education and Research Foundation.