体内研究 Bay 11-7082 对子宫肌瘤生长和基因表达的影响：一项临床前研究。
In Vivo Effects of Bay 11-7082 on Fibroid Growth and Gene Expression: A Preclinical Study.
机构信息
The Lundquist Institute for Biomedical Innovation, Torrance, CA 90502, USA.
Department of Obstetrics and Gynecology, David Geffen School of Medicine at University of California, Los Angeles, CA 90024, USA.
出版信息
Cells. 2024 Jun 24;13(13):1091. doi: 10.3390/cells13131091.
Current medical therapies for fibroids have major limitations due to their hypoestrogenic side effects. Based on our previous work showing the activation of NF-kB in fibroids, we hypothesized that inhibiting NF-kB in vivo would result in the shrinkage of tumors and reduced inflammation. Fibroid xenografts were implanted in SCID mice and treated daily with Bay 11-7082 (Bay) or vehicle for two months. Bay treatment led to a 50% reduction in tumor weight. RNAseq revealed decreased expression of genes related to cell proliferation, inflammation, extracellular matrix (ECM) composition, and growth factor expression. Validation through qRT-PCR, Western blotting, ELISA, and immunohistochemistry (IHC) confirmed these findings. Bay treatment reduced mRNA expression of cell cycle regulators (, , and ), inflammatory markers (, , , , , , , , and ), ECM remodelers (, , , and ), growth factors (, , and ), progesterone receptor, and miR-29c and miR-200c. Collagen levels were reduced in Bay-treated xenografts. Western blotting and IHC showed decreased protein abundance in certain ECM components and inflammatory markers, but not cleaved caspase three. Ki67, CCND1, and E2F1 expression decreased with Bay treatment. This preclinical study suggests NF-kB inhibition as an effective fibroid treatment, suppressing genes involved in proliferation, inflammation, and ECM remodeling.
目前治疗子宫肌瘤的医学疗法存在重大局限性，因为它们具有低雌激素副作用。基于我们之前的研究表明 NF-kB 在子宫肌瘤中的激活，我们假设体内抑制 NF-kB 会导致肿瘤缩小和炎症减轻。将纤维瘤异种移植物植入 SCID 小鼠中，并每天用 Bay 11-7082（Bay）或载体治疗两个月。Bay 治疗导致肿瘤重量减少 50%。RNAseq 显示与细胞增殖、炎症、细胞外基质（ECM）组成和生长因子表达相关的基因表达降低。通过 qRT-PCR、Western blotting、ELISA 和免疫组织化学（IHC）验证了这些发现。Bay 治疗降低了细胞周期调节剂（、、和）、炎症标志物（、、、、、、、和）、ECM 重塑剂（、、、和）、生长因子（、和）、孕激素受体以及 miR-29c 和 miR-200c 的 mRNA 表达。Bay 处理的异种移植物中的胶原水平降低。Western blotting 和 IHC 显示某些 ECM 成分和炎症标志物的蛋白丰度降低，但 cleaved caspase three 没有降低。Ki67、CCND1 和 E2F1 的表达随 Bay 治疗而降低。这项临床前研究表明 NF-kB 抑制作为一种有效的子宫肌瘤治疗方法，抑制与增殖、炎症和 ECM 重塑相关的基因。
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