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

<b>Background/Objectives:</b> We have previously identified <i>let-7f-5p</i>, <i>miR-10b-5p</i>, <i>miR-34a-5p</i>, <i>miR-181b-5p</i>, and <i>miR-181d-5p</i> 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 <i>miR-34a</i> and <i>miR-181b</i> in uterine LM and LMS cells. <b>Methods:</b> All the selected miRNAs showed downregulation in LMS cells compared to LM cells, but only <i>miR-34a</i> and <i>miR-181b</i> expression patterns matched those of patient samples. Therefore, these two miRs were selected for further analyses. <b>Results:</b> Loss of function analysis demonstrated that <i>miR-34a</i> and <i>miR-181b</i> silencing inhibited LM cell proliferation and migration. <i>MiR-34a</i> silencing induced <i>CCND1</i> and <i>MDM4</i> expression and inhibited <i>KMT2D</i>, <i>BCL2</i>, and <i>NOTCH2</i> in LM. Silencing of <i>miR-181b</i> promotes <i>TIMP3</i> and <i>FGFR1</i> expression in LM and diminishes <i>BCL2</i>, <i>NOTCH2</i>, <i>ATM</i>, <i>IRS1</i>, and <i>PRLR</i>. Gain of function analysis revealed that the introduction of <i>miR-34a</i> and <i>miR-181b</i> mimics suppressed proliferation and migration in malignant LMS cells. Additionally, transfection with a <i>miR-34a</i> mimic downregulated <i>NOTCH2</i> and <i>BCL2</i> expression and enhanced the expression of <i>CCND1</i>, <i>KMT2D</i>, and <i>TP53</i> in LMS cells. Moreover, <i>miR-181b</i> overexpression decreased <i>TIMP3</i>, <i>NOTCH2</i>, <i>ATM</i>, and <i>IRS1</i> expression and increased the expression of <i>FGFR1</i> in this cell. Importantly, the single introduction of either a <i>miR-34a</i> or <i>miR-181b</i> mimic was able to decrease the invasion capacity of LMS cells. <b>Conclusions:</b> Our studies demonstrated that <i>miR-34a</i> or <i>miR-181b</i> 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.