Saxena Sharad, Volpe Maria Concetta, Agostinis Chiara, Vodret Simone, Ring Nadja Anneliese Ruth, Colliva Andrea, Vuerich Roman, Braga Luca, Cook-Calvete A, Romano Federico, Zito Gabriella, Lorenzo Giovanni Di, Ura Blendi, Ricci Giuseppe, Pinamonti Maurizio, Bulla Roberta, Zacchigna Serena
Cardiovascular Biology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
Cardiovascular Biology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy; Functional Biology Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy; Department of Life Sciences, University of Trieste, Trieste, Italy.
Biomed Pharmacother. 2025 Apr;185:117946. doi: 10.1016/j.biopha.2025.117946. Epub 2025 Feb 28.
Uterine leiomyomas arise from altered uterine smooth muscle cell proliferation in the myometrium. Available treatments are limited and fraught with major side effects. Here, we leveraged data from a high-throughput screening using human microRNA mimics and selected miR-148a-3p as a therapeutic target. The study aimed to assess the therapeutic potential of a miR-148a-3p inhibitor in suppressing the proliferation of uterine leiomyoma cells and in a xenograft mouse model.
Clinical samples of uterine leiomyoma were used to isolate primary uterine leiomyoma cells and develop a subcutaneous xenograft mouse model. Cells were transfected with both miR-148a-3p mimic and anti-miR-148a-3p to assess the effect of miR-148a-3p on-cell proliferation. Animals were administered anti-miR-148a-3p-LNA via both local (intra-tumoral) and systemic (intraperitoneal) routes. Tumor volume was measured using ultrasonography, followed by histological and immunofluorescence staining, and target gene expression analysis.
Transfection of primary cells with miR-148a-3p mimic resulted in increased smooth-muscle cell proliferation, whereas anti-miR-148a-3p LNA reduced their proliferation. Both local and systemic delivery of anti-miR-148a-3p LNA reduced tumor volume and cell proliferation. Anti-miR-148a-3p LNA also led to reduced levels of miR-148a-3p in vivo, paralleled by the up-regulation of its target genes TXNIP and Nrp1.
Anti-miR-148a-3p LNA inhibits the proliferation of patient-derived leiomyoma cells and tumor growth in vivo, by suppressing miR-148a-3p levels and increasing TXNIP and Nrp1 gene expression. The highest therapeutic effect was observed with systemic administration, positioning miR-148a-3p inhibition as a promising therapeutic strategy for uterine leiomyoma in humans.
子宫平滑肌瘤源于子宫肌层中子宫平滑肌细胞增殖异常。现有治疗方法有限且伴有严重副作用。在此，我们利用了一项使用人微小RNA模拟物进行的高通量筛选数据，并选择miR-148a-3p作为治疗靶点。本研究旨在评估miR-148a-3p抑制剂在抑制子宫平滑肌瘤细胞增殖以及在异种移植小鼠模型中的治疗潜力。
使用子宫平滑肌瘤的临床样本分离原代子宫平滑肌瘤细胞并建立皮下异种移植小鼠模型。用miR-148a-3p模拟物和抗miR-148a-3p转染细胞，以评估miR-148a-3p对细胞增殖的影响。通过局部（瘤内）和全身（腹腔内）途径给动物施用抗miR-148a-3p-LNA。使用超声测量肿瘤体积，随后进行组织学和免疫荧光染色以及靶基因表达分析。
用miR-148a-3p模拟物转染原代细胞导致平滑肌细胞增殖增加，而抗miR-148a-3p LNA降低了它们的增殖。局部和全身递送抗miR-148a-3p LNA均降低了肿瘤体积和细胞增殖。抗miR-148a-3p LNA还导致体内miR-148a-3p水平降低，同时其靶基因TXNIP和Nrp1上调。
抗miR-148a-3p LNA通过抑制miR-148a-3p水平并增加TXNIP和Nrp1基因表达，抑制患者来源的平滑肌瘤细胞增殖和体内肿瘤生长。全身给药观察到最高治疗效果，将miR-148a-3p抑制定位为人类子宫平滑肌瘤的一种有前景的治疗策略。
