Abstract
MicroRNAs have been proved to participate in multiple biological processes in cancers. For developing resistance to cytotoxic drug, cancer cells, especially the cancer stem cells, usually change their microRNA expression profile to survive in hostile environments. In the present study, we found that expression of microRNA-27a was increased in colorectal cancer stem cells. High level of microRNA-27a was indicated to induce the resistance to TNF-related apoptosis-inducing ligand (TRAIL). Knockdown of microRNA-27a resensitized colorectal cancer stem cells to TRAIL-induced cell death. Mechanically, the gene of Apaf-1, which is associated with the mitochondrial apoptosis, was demonstrated to be the target of microRNA-27a in colorectal cancer stem cells. Knockdown of microRNA-27a increased the expression level of Apaf-1, thus enhancing the formation of Apaf-1-caspase-9 complex and subsequently promoting the TRAIL-induced apoptosis in colorectal cancer stem cells. These findings suggested that knockdown of microRNA-27a in colorectal cancer stem cells by the specific antioligonucleotides was potential to reverse the chemoresistance to TRAIL. It may represent a novel therapeutic strategy for treating the colorectal cancer more effectively.
Highlights
Colorectal cancer represents the third most common cancer around the world [1]
Knockdown of microRNA-27a increased the expression level of Apoptotic protease activating factor-1 (Apaf-1), enhancing the formation of Apaf-1-caspase-9 complex and subsequently promoting the TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in colorectal cancer stem cells. These findings suggested that knockdown of microRNA-27a in colorectal cancer stem cells by the specific antioligonucleotides was potential to reverse the chemoresistance to TRAIL
We found that colorectal cancer stem cells (CSCs) showed strongly higher level of miR-27a rather than their corresponding non-CSCs (Figure 1C)
Summary
Colorectal cancer represents the third most common cancer around the world [1]. Because of the liver metastases in early stage, colorectal cancer is realized as the “leading killer”, which has become a serious threat to human life and health [2, 3]. For treatment of colorectal cancer, chemotherapy is efficient initially. As the continuous use of anti-tumor drugs, colorectal cancer cells show lower response to them gradually [4]. Studies demonstrate that cancer stem cells (CSCs) are responsible for drug-resistance in various cancers [5,6,7], which emphasizes the significance of targeting CSCs in cancer therapy. CSCs are highly self-renewing and tumorigenic cells in tumor. They show obvious chemoresistance and play key roles in chemotherapy failure and cancer relapse [8, 9]. It is urgent to explore the mechanism by which colorectal CSCs develop their resistance to anti-tumor drugs for improving the efficiency of cancer therapy
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