Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like protein that conjugates to its target proteins to modify them through ISGylation, but the relevance of ISG15 expression and its effects have been not completely defined. Herein, we examined the interplay between ISG15/ISGylation and the interferon-gamma (IFN-γ) signaling pathway in mammary tumors and compared it with that in normal mammary tissues. Our results indicated that mammary tumors had higher levels of ISG15 mRNA and ISG15 protein than the adjacent normal mammary tissue. Furthermore, the expression of IFN-γ signaling components was altered in breast cancer. Interestingly, IFN-γ treatment induced morphological changes in MCF-7 and MDA-MB-231 breast cancer cell lines due to cytoskeletal reorganization. This cellular process seems to be related to the increase in ISGylation of cytoplasmic IQ Motif Containing GTPase Activating Protein 1 (IQGAP1). Interactome analysis also indicated that IFN-γ signaling and the ISGylation system are associated with several proteins implicated in cytoskeletal remodeling, including IQGAP1. Thus, ISG15 may present a potential biomarker for breast cancer, and IFN-γ signaling and protein ISGylation may participate in the regulation of the cytoskeleton in breast cancer cells.

干扰素刺激的基因15（ISG15）是一种遍在蛋白样蛋白，与目标蛋白缀合以通过ISGylation对其进行修饰，但是ISG15表达的相关性及其作用尚未完全确定。在这里，我们检查了乳腺肿瘤中ISG15 / ISGylation与干扰素-γ（IFN-γ）信号通路之间的相互作用，并将其与正常乳腺组织中的相互作用进行了比较。我们的结果表明，乳腺肿瘤的ISG15水平更高mRNA和ISG15蛋白高于邻近的正常乳腺组织。此外，在乳腺癌中IFN-γ信号传导成分的表达发生了改变。有趣的是，由于细胞骨架重组，IFN-γ治疗诱导了MCF-7和MDA-MB-231乳腺癌细胞系的形态变化。此细胞过程似乎与包含GTPase激活蛋白1（IQGAP1）的胞质IQ基序的ISGylation增加有关。相互作用分析还表明，IFN-γ信号传导和ISGylation系统与涉及细胞骨架重塑的几种蛋白质（包括IQGAP1）有关。因此，ISG15可能是乳腺癌的潜在生物标志物，而IFN-γ信号转导和蛋白质ISGylation可能参与乳腺癌细胞中细胞骨架的调节。