MON-310 Oncogenic Roles of Tripartite Motif 25 in Endometrial Cancer

Abstract

The tripartite motif (TRIM) family proteins are known for their structure typically composed of integrated three components of RING, B-box and coiled-coil domains. Some of the TRIM proteins have been paid attention as they contribute to the development and progression of cancers. We previously identified that TRIM25/Efp promotes breast cancer proliferation by exerting its E3 ubiquitin ligase function to degrade a cell cycle checkpoint 14-3-3σ. TRIM25 also plays a critical role in antiviral immunity and interferon production by interacting with the DExD/H box RNA helicase family proteins. During the antiviral signaling, TRIM25 is involved in the activation of transcription factors such as nuclear factor κB (NF-κB). In the present study, we investigated whether TRIM25 contributes to the pathophysiology of endometrial cancer, one of the major gynecological tumors with an increasing incidence especially among postmenopausal women. In both estrogen receptor (ER)-positive and -negative endometrial cancer cells, the knockdown of TRIM25 substantially repressed the cell proliferation and migration. As expected, TRIM25 knockdown in endometrial cancer cells increased 14-3-3σ protein levels and decreased the cell population at proliferative stage. Moreover, TRIM25-specific siRNAs could successfully suppress the in vivo tumor growth of endometrial cancer cells in both subcutaneous and orthotopic xenograft models. Microarray analysis showed that genes involved in NF-κB-dependent pathway were particularly downregulated in endometrial cancer treated with TRIM25-specific siRNAs. Stable expression of TRIM25 substantially promoted the proliferation of endometrial cancer cells. Taken together, TRIM25 plays an oncogenic role in endometrial cancer by modulating 14-3-3σ protein degradation and NF-κB pathway. TRIM25 and its interacting factors would be potential diagnostic and therapeutic targets for clinical management of endometrial cancer.