The deoxycholic acid targets miRNA-dependent CAC1 gene expression in multidrug resistance of human colorectal cancer.
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.
Department of Oncology, First Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. yingkong76@gmail.com
Ying
Y
Kong
Pei-Song
PS
Bai
Hong
H
Sun
Ke-Jun
KJ
Nan
Nan-Zheng
NZ
Chen
Xiao-Gai
XG
Qi
D020413:3' Untranslated Regions; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism; D003840:Deoxycholic Acid / Q000494:pharmacology / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D034622:RNA Interference; D059467:Transcriptome; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D020413:3' Untranslated Regions; D000903:Antibiotics, Antineoplastic; C546534:CACUL1 protein, human; D044842:Cullin Proteins; D035683:MicroRNAs; C531408:mirn199 microRNA, human; D003840:Deoxycholic Acid; D004317:Doxorubicin