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Abstract：
Pinin (PNN) is a desmosome-associated protein that reinforces the organization of keratin intermediate filaments and stabilizes the anchoring of the cytoskeleton network to the lateral surface of the plasma membrane. The aberrant expression of PNN affects the strength of cell adhesion as well as modifies the intracellular signal transduction pathways leading to the onset of CRC. In our previous studies, we characterized the role of miR-195-5p in the regulation of desmosome junctions and in CRC progression. Here, with the aim of investigating additional mechanisms related to the desmosome complex, we identified PNN as a miR-195-5p putative target. Using a public data repository, we found that PNN was a negative prognostic factor and was overexpressed in colon cancer tissues from stage 1 of the disease. Then, we assessed PNN expression in CRC tissue specimens, confirming the overexpression of PNN in tumor sections. The increase in intracellular levels of miR-195-5p revealed a significant decrease in PNN at the mRNA and protein levels. As a consequence of PNN regulation by miR-195-5p, the expression of KRT8 and KRT19, closely connected to PNN, was affected. Finally, we investigated the in vivo effect of miR-195-5p on PNN expression in the colon of AOM/DSS-treated mice. In conclusion, we have revealed a new mechanism driven by miR-195-5p in the regulation of desmosome components, suggesting a potential pharmacological target for CRC therapy.
摘要：
Pinin（PNN）是一种桥粒相关蛋白，可增强角蛋白中间丝的组织，并稳定细胞骨架网络与质膜侧面的锚定。PNN的异常表达会影响细胞粘附的强度，并改变导致CRC发作的细胞内信号转导途径。在我们之前的研究中,我们表征了miR-195-5p在桥粒连接调节和CRC进展中的作用.这里,为了研究与桥粒复合体相关的其他机制，我们将PNN确定为miR-195-5p的推定靶标.使用公共数据存储库，我们发现,PNN是一个负预后因子,并且在1期结肠癌组织中过度表达.然后，我们评估了CRC组织标本中的PNN表达，证实PNN在肿瘤切片中的过表达。miR-195-5p细胞内水平的增加揭示了mRNA和蛋白质水平的PNN的显著降低。作为miR-195-5p调节PNN的结果，与PNN紧密相连的KRT8和KRT19的表达式，受到影响。最后,我们研究了miR-195-5p对AOM/DSS处理小鼠结肠中PNN表达的体内影响。总之,我们揭示了由miR-195-5p驱动的桥粒组分调控的新机制，提示CRC治疗的潜在药理靶点。
