Could let-7f, miR-10b, miR-34a, miR-181b, and miR-181d Be Useful Tools as a Target Therapy for Uterine Leiomyosarcoma?

Background/

Objectives

We have previously identified let-7f-5p, miR-10b-5p, miR-34a-5p, miR-181b-5p, and miR-181d-5p as differentially expressed between uterine leiomyoma (LM) and leiomyosarcoma (LMS) tissue samples. The present study aimed to characterize these miRNA expression profiles and to assess the functional role of miR-34a and miR-181b in uterine LM and LMS cells.

Methods

All the selected miRNAs showed downregulation in LMS cells compared to LM cells, but only miR-34a and miR-181b expression patterns matched those of patient samples. Therefore, these two miRs were selected for further analyses.

Results

Loss of function analysis demonstrated that miR-34a and miR-181b silencing inhibited LM cell proliferation and migration. MiR-34a silencing induced CCND1 and MDM4 expression and inhibited KMT2D, BCL2, and NOTCH2 in LM. Silencing of miR-181b promotes TIMP3 and FGFR1 expression in LM and diminishes BCL2, NOTCH2, ATM, IRS1, and PRLR. Gain of function analysis revealed that the introduction of miR-34a and miR-181b mimics suppressed proliferation and migration in malignant LMS cells. Additionally, transfection with a miR-34a mimic downregulated NOTCH2 and BCL2 expression and enhanced the expression of CCND1, KMT2D, and TP53 in LMS cells. Moreover, miR-181b overexpression decreased TIMP3, NOTCH2, ATM, and IRS1 expression and increased the expression of FGFR1 in this cell. Importantly, the single introduction of either a miR-34a or miR-181b mimic was able to decrease the invasion capacity of LMS cells.

Conclusions

Our studies demonstrated that miR-34a or miR-181b may play an anti-oncogenic role in uterine tumors; further studies are needed to better understand the role and regulatory mechanism of these miRNAs in LMS cancer development, which will help provide prognostic and therapeutic options for patients with LMS.