miR-25 targets TNF-related apoptosis inducing ligand (TRAIL) death receptor-4 and promotes apoptosis resistance in cholangiocarcinoma.
Hepatology (Baltimore, Md.)
It has been established that microRNA expression and function contribute to phenotypic features of malignant cells, including resistance to apoptosis. Although targets and functional roles for a number of microRNAs have been described in cholangiocarcinoma, many additional microRNAs dysregulated in this tumor have not been assigned functional roles. In this study, we identify elevated miR-25 expression in malignant cholangiocarcinoma cell lines as well as patient samples. In cultured cells, treatment with the Smoothened inhibitor, cyclopamine, reduced miR-25 expression, suggesting Hedgehog signaling stimulates miR-25 production. Functionally, miR-25 was shown to protect cells against TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Correspondingly, antagonism of miR-25 in culture sensitized cells to apoptotic death. Computational analysis identified the TRAIL Death Receptor-4 (DR4) as a potential novel miR-25 target, and this prediction was confirmed by immunoblot, cell staining, and reporter assays.
CONCLUSION: These data implicate elevated miR-25 levels in the control of tumor cell apoptosis in cholangiocarcinoma. The identification of the novel miR-25 target DR4 provides a mechanism by which miR-25 contributes to evasion of TRAIL-induced cholangiocarcinoma apoptosis.
3' Untranslated Regions, Apoptosis, Bile Duct Neoplasms, Bile Ducts, Intrahepatic, Cell Line, Tumor, Cholangiocarcinoma, Gene Expression Regulation, Hedgehog Proteins, Humans, MicroRNAs, Receptors, TNF-Related Apoptosis-Inducing Ligand, Signal Transduction
This is the peer reviewed version of the following article: 39. Razumilava N, Bronk SF, Smoot RL, Fingas CD, Werneburg NW, Roberts LR, Mott JL*. (2012) miR-25 Targets TRAIL Death Receptor-4 and Promotes Apoptosis Resistance in Cholangiocarcinoma. Hepatology 55(2):465-75, which has been published in final form at 10.1002/hep.24698. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving
Razumilava, Nataliya; Bronk, Steve F.; Smoot, Rory L.; Fingas, Christian D.; Werneburg, Nathan W.; Roberts, Lewis R.; and Mott, Justin L., "miR-25 targets TNF-related apoptosis inducing ligand (TRAIL) death receptor-4 and promotes apoptosis resistance in cholangiocarcinoma." (2012). Journal Articles: Biochemistry & Molecular Biology. 19.