Downregulation of NRARP exerts anti-tumor activities in the breast tumor cells depending on Wnt/β-catenin-mediated signals: The role of miR-130a-3p,Chemical Biology & Drug Design

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Downregulation of NRARP exerts anti-tumor activities in the breast tumor cells depending on Wnt/β-catenin-mediated signals: The role of miR-130a-3p
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2022-07-07 , DOI: 10.1111/cbdd.14113
Jafar Poodineh ₁ , Majid Sirati‐Sabet ₂ , Masoumeh Rajabibazl ₃ , Majid Ghasemian ₂ , Samira Mohammadi‐Yeganeh _{4,

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Affiliation

The Notch-regulated ankyrin repeat protein (NRARP) functions as a molecular link between Notch and Wnt signaling pathways. Although it has recently been identified to be overexpressed in breast cancer (BC), the molecular mechanisms that regulate NRARP remain unknown. Since microRNAs (miRNAs) regulate gene expression post-transcriptionally, miRNA dysregulation could explain the abnormal gene expression. Here, we identified miR-130a-3p as an NRARP regulator and evaluated its effects on the behavior of BC cells. Quantitative real-time PCR was performed to assess the transcriptional levels of miR-130a-3p and NRARP in BC cells. Next, miR-130a-3p was transiently transfected into BC cells to assess its influence on NRARP expression. Owing to the positive regulatory effects of NRARP on the Wnt/β-catenin signaling pathway, we also analyzed the expression levels of five Wnt/β-catenin pathway genes and one downstream target gene in BC cells. We then assessed anti-tumor activities of miR-130a-3p in BC cells using the MTT proliferation assay, the soft agar colony formation assay for anchorage-independent growth (AIG), as well as scratch and transwell assays for cell migration. The results showed that miR-130a-3p was downregulated in BC cells, whereas NRARP was upregulated. Overexpression of miR-130a-3p inhibited the expression of NRARP and some Wnt/β-catenin signaling pathway genes, as well as exerted anti-tumor effects as evidenced by decreased cell proliferation, AIG, and migration of BC cells. In conclusion, the tumor-suppressive function of miR-130a-3p in BC may be mediated by inhibiting NRARP and Wnt/β-catenin signaling pathway. As a result, miR-130a-3p could be introduced as a therapeutic target for miRNA therapy in BC.

中文翻译：

NRARP 的下调在乳腺肿瘤细胞中发挥抗肿瘤活性取决于 Wnt/β-catenin 介导的信号：miR-130a-3p 的作用

Notch 调节的锚蛋白重复蛋白 ( NRARP ) 作为 Notch 和 Wnt 信号通路之间的分子链接。尽管最近发现它在乳腺癌 (BC) 中过度表达，但调节NRARP的分子机制仍然未知。由于 microRNA (miRNA) 在转录后调节基因表达，因此 miRNA 失调可以解释异常的基因表达。在这里，我们将 miR-130a-3p 鉴定为NRARP调节剂，并评估其对 BC 细胞行为的影响。进行定量实时 PCR 以评估BC 细胞中 miR-130a-3p 和NRARP的转录水平。接下来，将 miR-130a-3p 瞬时转染到 BC 细胞中以评估其对NRARP的影响表达。由于NRARP对 Wnt/β-catenin 信号通路的正向调节作用，我们还分析了 BC 细胞中 5 个 Wnt/β-catenin 通路基因和 1 个下游靶基因的表达水平。然后，我们使用 MTT 增殖试验、用于锚定非依赖性生长 (AIG) 的软琼脂集落形成试验以及用于细胞迁移的划痕和 transwell 试验评估了 BC 细胞中 miR-130a-3p 的抗肿瘤活性。结果显示miR-130a-3p在BC细胞中下调，而NRARP上调。miR-130a-3p的过表达抑制了NRARP的表达和一些 Wnt/β-catenin 信号通路基因，以及发挥抗肿瘤作用，如减少细胞增殖、AIG 和 BC 细胞迁移所证明的。总之，miR-130a-3p在BC中的抑癌功能可能是通过抑制NRARP和Wnt/β-catenin信号通路介导的。因此，可以引入 miR-130a-3p 作为 BC 中 miRNA 治疗的治疗靶点。

更新日期：2022-07-07

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