Abstract Introduction: Leiomyoma (LM) and leiomyosarcoma (LMS) are uterine mesenchymal tumors that present variable clinical behavior. LM are extremely common estrogen and progesterone dependent benign tumors. On the other hand, LMS are rare and aggressive malignant tumors with limited available treatment options. FoxO3a seems to have a tumor suppressor role and its loss of function may determine deregulation in the cell proliferation, with DNA damage accumulation. Several studies demonstrated FoxO3a with an important role in several tumors development; however, its regulation or function is unknown in uterine mesenchymal tumors. Objective: Here, our goals were to assess the FoxO3a expression profile in uterine LM and LMS, to evaluate the mechanisms involved on FoxO3a regulation, and to assess its use as a marker for diagnosis, prognosis and malignancy risk prediction. Methods: Formalin-Fixed Paraffin-Embedded tissues of 56 leiomyosarcomas (LMS), 80 leiomyomas (LM) and 20 myometrium (MM) from patients, were used for FOXO3a protein evaluation by immunohistochemistry (IHQ). Epigenetic regulation of FoxO3a expression was assessed by 84 miRNAs gene analysis, using Real Time PCR method (MIHS 109Z, Qiagen). MM, LM and LMS cells were evaluated for FoxO3a gene expression by Real Time PCR. Results: FOXO3a protein showed an increased expression profile in MM, LM and LMS. Higher protein levels were observed in the comparison between LMS and MM (p<0,05). Gene expression analysis corroborate the protein data, with higher FoxO3a expression in LMS compared to MM and LM cells. Concerning the miRNAs analysis, we found oncogenic has-96-5p and has-155-5p overexpressed in LMS samples (p=0,008 and p=0,0007; respectively), while the tumor suppressor miR-let7c-5p was down expressed (p=0.0026). Conclusion: FoxO3a seems to display an oncogenic role in uterine tumors and could participate in the tumors risk of malignancy. miRNAs expression profile corroborates the FoxO3a negative regulation in these tumors. However, further studies are necessary for the understanding of the FoxO3a role in LM and LMS biology. Citation Format: Natalia Garcia, Anamaria Ritti Ricci, Bruna Cristine de Almeida, Thais Gomes Almeida, Isabela Werneck Cunha, Edmund Chada Baracat, Kátia Candido Carvalho. Involvement of miRNA expression may contribute for FoxO3a oncogenic role in uterine leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 541.