MDM4 is targeted by miR-449b-5p to promote the proliferation of endometrial carcinoma

J. Zhao, X. Dong, S.-J. Tao, X.-L. Liu, Z. Li, J.-M. Liu, Y. Chen

Department of Reproductive Center, Jinan Second Women’s Protection Hospital, Jinan, China. jnsdefybjybgs@jn.shandong.cn

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• Oncology

OBJECTIVE: Previous studies have shown the involvement of microRNA-449b-5p (miR-449b-5p) and MDM4 in tumor development. This study aims to illustrate the role of miR-449b-5p in inhibiting proliferative capacity of endometrial carcinoma (EC) by targeting MDM4.

PATIENTS AND METHODS: Expression levels of miR-449b-5p and MDM4 in tumor tissues and paracancerous ones of EC patients were determined. Relationships between their levels and clinical parameters of EC patients were analyzed. Subsequently, regulatory effects of miR-449b-5p and MDM4 on proliferative capacities in KLE and HEC-1B cells were assessed by cell counting kit-8 (CCK-8) and colony formation assay, respectively. Thereafter, in vivo xenograft models were established in nude mice administrated with KLE cells overexpressing MDM4 or those with miR-449b-5p knockdown. Then, tumor weight and tumor volume were measured after mouse sacrifice. Finally, the interaction between miR-449b-5p and MDM4 was explored by Luciferase assay.

RESULTS: It was found that MDM4 was upregulated and miR-449b-5p was downregulated in EC tissues. Highly expressed MDM4 and lowly expressed miR-449b-5p were unfavorable to prognosis in EC patients, manifesting as a larger tumor size, more advanced tumor stage and lower overall survival. Besides, overexpression of MDM4 enhanced in vitro proliferative capacity in EC cells and in vivo tumorigenesis in nude mice bearing EC. Similarly, knockdown of miR-449b-5p yielded similar results. Luciferase assay confirmed that MDM4 was the target gene binding to miR-449b-5p, and its level was negatively correlated with miR-449b-5p level in EC.

CONCLUSIONS: MiR-449b-5p and MDM4 are downregulated and upregulated in EC species, respectively. They are closely linked to tumor size, tumor stage and overall survival in EC patients. Through negatively regulating MDM4 level, miR-449b-5p inhibits proliferative capacity in EC cells.

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