The deoxycholic acid targets miRNA-dependent CAC1 gene expression in multidrug resistance of human colorectal cancer |
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| Authors: | Ying Kong Pei-song Bai Hong Sun Ke-jun Nan Nan-zheng Chen Xiao-gai Qi |
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| Institution: | 1. Alzheimer''s Disease Center, University of Alabama at Birmingham, Birmingham, AL, USA;2. Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA;3. Department of Neurology, Birmingham VA Medical Center, Birmingham, AL, USA;4. Department of Neurology, Ralph H. Johnson VA Medical Center, Medical University of South Carolina, Charleston, SC, USA;5. Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA;6. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL, USA;7. Dominantly Inherited Alzheimer''s Network, Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA;8. Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA;1. Department of Hepatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, Kunming City, Yunnan Province, PR China;2. Department of Anesthesiology, Shanghai Ninth People''s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China;3. Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical College, Zunyi City, Guzhou Province, PR China;1. Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden;2. Department of Biosciences and Medical Nutrition, Karolinska Institute, Huddinge, Sweden |
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| Abstract: | There is evidence indicating that bile acid is a promoter of colorectal cancer. Deoxycholic acid modifies apoptosis and proliferation by affecting intracellular signaling and gene expression. We are interested in revealing the relationship between deregulated miRNAs and deoxycholic acid in colorectal cancer development. We found that miR-199a-5p was expressed at a low level in human primary colonic epithelial cells treated with deoxycholic acid compared with control, and miR-199a-5p was significantly down-regulated in colorectal cancer tissues. The miR-199a-5p expression in colorectal cancer cells led to the suppression of tumor cell growth, migration and invasion. We further identified CAC1, a cell cycle-related protein expressed in colorectal cancer, as a miR-199a-5p target. We demonstrated that CAC1 is over-expressed in malignant tumors, and cellular CAC1 depletion resulted in cancer growth suppression. HCT-8 cells transfected with a miR-199a-5p mimic or inhibitor had a decrease or increase in CAC1 protein levels, respectively. The results of the luciferase reporter gene analysis demonstrated that CAC1 was a direct miR-199a-5p target. The high miR-199a-5p expression and low CAC1 protein expression reverse the tumor cell drug resistance. We conclude that miR-199a-5p can regulate CAC1 and function as a tumor suppressor in colorectal cancer. Therefore, the potential roles of deoxycholic acid in carcinogenesis are to decrease miR-199a-5p expression and/or increase the expression of CAC1, which contributes to tumorigenesis in patients with CRC. These findings suggest that miR-199a-5p is a useful therapeutic target for colorectal cancer. |
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