MicroRNA-149, a p53-responsive microRNA, functions as an oncogenic regulator in human melanoma

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-09, Vol.108 (38), p.15840-15845
• Main Authors: Jin, Lei, Hu, Wang Lai, Jiang, Chen Chen, Wang, Jia Xu, Han, Chuan Chun, Chu, Ping, Zhang, Lin Jie, Thorne, Rick F, Wilmott, James, Scolyer, Richard A, Hersey, Peter, Zhang, Xu Dong, Wu, Mian
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Apoptosis; Apoptosis - genetics; Biological Sciences; Blotting, Western; Cancer; Cell Line; Cell Line, Tumor; Cell lines; Cell survival; DNA repair; equipment maintenance and repair; Genes; glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; HCT116 Cells; Humans; Male; Mcl-1 protein; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Metastases; Metastasis; Mice; Mice, Nude; MicroRNA; MicroRNAs - genetics; miRNA; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Transplantation; p53 protein; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogenes - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Stress; Three prime untranslated regions; Transformation; Transplantation, Heterologous; Tumor suppressor genes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Up regulation; Xenografts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1019312108

The tumor suppressor p53 is activated in response to cellular stress to prevent malignant transformation by activation of the DNA repair machinery to preserve the cell, or by induction of apoptosis to eliminate the cell should the damage prove irrevocable. The gene encoding p53 frequently undergoes inactivating mutations in many human cancers, but WT p53 is often expressed at high levels in melanoma, which, as judged from the malignant nature of the disease, fails to act as an effective tumor suppressor. Here we show that p53 directly up-regulates microRNA-149* (miR-149*) that in turn targets glycogen synthase kinase-3α, resulting in increased expression of Mcl-1 and resistance to apoptosis in melanoma cells. Although deficiency in miR-149* undermined survival of melanoma cells and inhibited melanoma growth in a mouse xenograft model, elevated expression of miR-149* was found in fresh human metastatic melanoma isolates, which was associated with decreased glycogen synthase kinase-3α and increased Mcl-1. These results reveal a p53-dependent, miR-149*–mediated pathway that contributes to survival of melanoma cells, provides a rational explanation for the ineffectiveness of p53 to suppress melanoma, and identifies the expression of miR-149* as a mechanism involved in the increased expression of Mcl-1 in melanoma cells.