National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013 Castellana Grotte, BA, Italy.
Int J Mol Sci. 2024 May 30;25(11):5980. doi: 10.3390/ijms25115980.
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.
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黏附的强度，并改变导致 CRC 发生的细胞内信号转导途径。在我们之前的研究中，我们描述了 miR-195-5p 在调节桥粒连接和 CRC 进展中的作用。在这里，为了研究与桥粒复合体相关的其他机制，我们将 PNN 鉴定为 miR-195-5p 的一个假定靶标。使用公共数据库，我们发现 PNN 是一个负预后因素，并且在疾病 1 期的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，证实了肿瘤切片中 PNN 的过表达。miR-195-5p 细胞内水平的增加导致 PNN 在 mRNA 和蛋白水平上的显著下调。由于 miR-195-5p 对 PNN 的调节，与 PNN 紧密相连的 KRT8 和 KRT19 的表达受到影响。最后，我们研究了 miR-195-5p 在 AOM/DSS 处理的小鼠结肠中对 PNN 表达的体内影响。总之，我们揭示了 miR-195-5p 调节桥粒成分的新机制，为 CRC 治疗提供了一个潜在的药物靶点。
