Abstract 1123: OncomiR-569 hit p53 pathway and deregulate proliferation of ovarian epithelial cells.
Authors: Raghavan Pradeep , Zhang Fan , Pradeep Sunila , Lu Yiling , Borresen-Dale Anne-Lise , Flores Elsa , Sood Anil , Mills Gordon 
Published: August 2014

Background

The 3q26.2 loci amplification is present in a large proportion of high grade serous epithelial ovarian cancer (HGSEOC) is less frequently curable disease in the clinic. The 3q26.2 loci, which is present in at least 35% of HGSEOC, is large and structurally complex suggesting that multiple coding genes of the amplicon contribute to tumor initiation and progression either alone or through cooperative activity. Our high resolution SNP array mapping of 3q26.2 amplicon identified a microRNA named miR-569 is highly amplified in addition to the coding genes in a large set of ovarian cancer samples. Potential role of miR-569 is not characterized previously in the context of ovarian cancer and our study provide mechanism underlying the oncogenic role of miR569 in ovarian cancer.

Results

We demonstrated a strong correlation between 3q26.2 amplification and overexpression of miR569 in patient's samples of ovarian cancer. Importantly overexpression and knockdown of miR569 in normal epithelial cells altered their growth, proliferation, and lumen filling in 3-dimensional culture models in Matrigel. Ectopic expression of miR569 in epithelial cancer cells promoted tumor growth and metastatic potential of tumor cells in mouse xenograft models. In silico and in vitro experiments showed that miR-569 directly target and inhibited the expression of p53 induced tumor suppressor gene TP53INP1. TP53INP1 is transcriptionally regulated by p53 or p73 proteins, however miR-569 is a key post-transcriptional regulator of TP53INP1 expression independent of p53 or p73 proteins. Immunohistochemical and protein array analysis confirmed that TP53INP1 protein levels were higher in normal tissues compared to cancer tissues of breast and ovary. Reduced expression of TP53INP1 mRNA and protein were associated with worsened outcomes and promoted distant metastasis in the clinic. In consistent with our in vitro results, in vivo targeting of miR-569 markedly reduced tumor growth and metastatic spreads.

Discussion

Our studies combined with previous literature are compatible with a model wherein amplification of 3q26.2 increases miR569 levels resulting in decreased TP53INP1 levels independently of p53 or p73 function. Such a decrease in TP53INP1 subsequently reduces p53 phosphorylation resulting in a positive feedback loop and collapse the p53-mediated cell cycle regulation. Based on our preclinical results of antimiR-569 on cell survival, tumor growth and drug sensitivity inhibiting miR-569 activity or increasing TP53INP1 may be a valid therapeutic target to treat ovarian cancer.

Citation Format: Pradeep Raghavan, Fan Zhang, Sunila Pradeep, Yiling Lu, Anne-Lise Borresen-Dale, Elsa Flores, Anil Sood, Gordon Mills. OncomiR-569 hit p53 pathway and deregulate proliferation of ovarian epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1123. doi:10.1158/1538-7445.AM2013-1123