Li Santi Anna, Alfieri Mariaevelina, Meo Luigia, Ragno Pia
Department of Chemistry and Biology, University of Salerno, 84084 Fisciano (Salerno), Italy.
Clinical Pathology, Pausilipon Hospital, A.O.R.N Santobono-Pausilipon, 80129 Naples, Italy.
Cells. 2025 Apr 22;14(9):623. doi: 10.3390/cells14090623.
The urokinase-receptor (uPAR) exerts multiple functions supporting most cancer hallmarks. Increased uPAR expression is associated with an unfavorable prognosis in several cancer types, including hematologic malignancies. We previously reported that three oncosuppressor microRNAs (miRNAs) can target the 3'untranslated region (3'UTR) of the uPAR mRNA and that uPAR mRNA is a competitive endogenous RNA (ceRNA) able to recruit oncosuppressor miRs, thus impairing their activity. We now show that uPAR mRNA can also be targeted by oncosuppressor members of the let-7 miRNA family in acute myeloid leukemia (AML) cell lines. Indeed, let-7a, let7d and let-7g directly target the 3'UTR of uPAR mRNA, thus down-regulating uPAR expression. These let-7 miRNAs are expressed in KG1 and U937 AML cells; their levels are high in KG1 cells, which express low uPAR levels, and low in the U937 cell line, expressing high levels of uPAR. Overexpression of these miRNAs down-regulates uPAR expression and impairs the adhesion to fibronectin and migration of U937 cells, without affecting their proliferation. Accordingly, the overexpression of specific inhibitors targeting these let-7 miRNAs efficiently increases uPAR expression in KG1 cells. These results indicate that selected let-7 miRNAs regulate uPAR expression and impair the adhesion and migration of AML cells.
尿激酶受体（uPAR）发挥多种功能，支持大多数癌症特征。uPAR表达增加与包括血液系统恶性肿瘤在内的多种癌症类型的不良预后相关。我们之前报道过，三种抑癌微小RNA（miRNA）可靶向uPAR mRNA的3'非翻译区（3'UTR），且uPAR mRNA是一种竞争性内源性RNA（ceRNA），能够募集抑癌miR，从而损害其活性。我们现在发现，在急性髓系白血病（AML）细胞系中，uPAR mRNA也可被let-7 miRNA家族的抑癌成员靶向。事实上，let-7a、let-7d和let-7g直接靶向uPAR mRNA的3'UTR，从而下调uPAR表达。这些let-7 miRNA在KG1和U937 AML细胞中表达；它们在表达低水平uPAR的KG1细胞中水平较高，而在表达高水平uPAR的U937细胞系中水平较低。这些miRNA的过表达下调了uPAR表达，并损害了U937细胞对纤连蛋白的黏附及迁移能力，但不影响其增殖。相应地，靶向这些let-7 miRNA的特异性抑制剂的过表达有效增加了KG1细胞中的uPAR表达。这些结果表明，特定的let-7 miRNA调节uPAR表达，并损害AML细胞的黏附与迁移能力。
