miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma

Alexzander Swarbrick, et al. 2010. Nat Med. 16, 1134-1141

Speaker: Yi-Wen Yang (楊逸紋)                           Time: 13:10~14:00, Dec. 22, 2010

Commentator: Dr. Pei-Jung Lu (呂佩融博士)     Place: Room 601

Abstract:

The p53 is a transcription factor that responds to genotoxic stresses, leading to cell cycle arrest, apoptosis or senescence. Approximately 50% of all tumors carry a p53 mutation, and others have inactive p53 function by various mechanisms. Therefore, scientists have attempted to reactivate p53 in cancer therapy. However, in some cancers such as more than 99% of primary neuroblastomas maintain wild-type p53, the mechanisms to attenuate p53 functoin remain unclear (1). MicroRNAs are gene regulators by binding to 3’UTR of the target, and studies suggest that miRNAs can function as either tumor suppressors or oncogenes (2). In the present study, the authors have identified a high homologous p53 3’UTR region which has two target sites for miR-380-5p. Using mouse embryonic stem cells which have intrinsic miR-380-5p as a model to examine the function of miR-380-5p, the authors showed that endogenous miR-380-5p could suppress p53 and apoptosis in embryonic stem cells. In addition, the ectopic expression of miR-380-5p in MCF10A cells, which have wild-type p53 but undetectable miR-380-5p, could suppress p53 effectively. Moreover, the in vivo results showed that the incidence of tumors increased in activated HRAS-expressing mouse model while treating with miR-380-5p. Both v-myc myelocytomatosis viral-related oncogene (MYCN)-transgenic mice and neuroblastoma cells from patients indicated that miR-380-5p attenuated p53 function in neuroblastoma. In conclusion, miR-380-5p is highly expressed in neuroblastoma, which is correlated with poor outcome in subjects with MYCN amplification. Finally, in order to know whether miR-380-5p may serve as a new target for neuroblastoma therapy, the authors analyzed the tumor formation in mice after miR-380-5p antagonist (anti-miR380) treatment. They found that systemic delivery of anti-miR380 decreased tumor growth. This article demonstrates a novel mechanism to regulate p53 in cancer and show a potential therapeutic target for neuroblastoma.

References:

1.      Deborah A. Tweddle, et al. 2003. The p53 pathway and its inactivation in neuroblastoma. Cancer Lett. 197, 93-98.

2.      Aurora Esquela-Kerscher and Frank J. Slack. 2006. Oncomirs—microRNAs with a role in cancer. Nat. Rev. Cancer 6, 259-269.