miR-25 Targets TNF-Related Apoptosis Inducing Ligand (TRAIL) Death Receptor-4 and Promotes Apoptosis Resistance in Cholangiocarcinoma

Abstract

It has been established that microRNA expression and function contribute to phenotypic features of malignant cells, including resistance to apoptosis. While 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 TRIAL-induced cholangiocarcinoma apoptosis.

Inhibition of microRNA-25 by tumor necrosis factor α is critical in the modulation of vascular smooth muscle cell proliferation

“…Thus, miR-25 may be a potential therapeutic target in the treatment of vascular disease. Previous studies have demonstrated that miR-25 is able to regulate various developmental and cellular processes, and is implicated in a number of human diseases (31)(32)(33). miR-25 is known to be important in several types of cancer, including hepatocellular carcinoma, and colon, gastric and lung cancer (34)(35)(36).…”

MicroRNA-92a Negatively Regulates Toll-like Receptor (TLR)-triggered Inflammatory Response in Macrophages by Targeting MKK4 Kinase

“…miR-25 belongs to the miR106b-25 cluster that was involved in development and tumorigenesis with the miR-17-92a cluster (57,58). miR-25 itself has been demonstrated to regulate apoptosis by targeting Bim in human ovarian cancer (59) and promote apoptosis resistance in cholangiocarcinoma by targeting NF-related apoptosis-inducing ligand (TRAIL) death receptor-4 (40). In addition, miR-25 with other miRNAs collectively influences MKK4 abundance during replicative senescence (60), but its function in innate immunity is unknown.…”

Circulating microRNA-125b and microRNA-130a expression profiles predict chemoresistance to R-CHOP in diffuse large B-cell lymphoma patients

“…However, ~20% of patients are not sensitive to this immunochemotherapy, and these patients then relapse following the first-line regimen and tend to respond poorly to additional chemotherapy lines. Studies suggest that abnormalities in signaling pathways including NF-YB, SFPQ, MYBL2, BIM/APAF-1, AEG-1, BCL-2, XIAP, DR4 and ABCA1 are involved in primary or acquired chemoresistance and poor prognosis (3)(4)(5)(6)(7)(8)(9). Therefore, the identification of chemoresistance-related biomarkers may achieve a better prediction of chemotherapy efficacy for DLBCL patients, and could be used for the diagnosis of poor outcome cases, providing an advanced treatment strategy.…”