肝细胞生长因子（HGF）在促进肿瘤迁移、侵袭和转移方面发挥着关键作用，部分是通过上调整合素来实现的。 HGF 如何促进整合素介导的肿瘤发生背后的分子机制尚不完全清楚。在这项研究中，我们证明泛素特异性肽酶 22 (USP22) 对于 HGF 诱导的黑色素瘤转移至关重要。 HGF 处理显着增加了 USP22 和多个整合素家族成员的表达，特别是 ITGAV、ITGB3 和 ITGA1。对 TCGA 数据库的公正分析表明，整合素是多种人类癌症类型中 USP22 和 HGF 的共同下游靶标。值得注意的是，CRISPR介导的USP22缺失完全消除了黑色素瘤细胞中HGF诱导的整合素表达。在分子水平上，USP22 充当 Sp1 的真正去泛素酶，Sp1 是 ITGAV、ITGB3 和 ITGA1 基因的转录因子。 USP22 与 Sp1 泛素化相互作用并抑制 Sp1 泛素化，防止 Sp1 蛋白酶体降解。免疫组织学分析检测到人类黑色素瘤组织中 USP22、Sp1 和整合素 αv 之间存在正相关性，支持了这一点。这项研究通过在黑色素瘤转移过程中使 Sp1 转录因子去泛素化，确定标志基因 USP22 的死亡是 HGF 诱导的整合素表达的关键正调节因子。版权所有 © 2024。由 Elsevier B.V. 出版。

Hepatocyte growth factor (HGF) plays a critical role in promoting tumor migration, invasion, and metastasis, partly by upregulating integrins. The molecular mechanisms behind how HGF facilitates integrin-mediated tumorigenesis are not fully understood. In this study, we demonstrate that the ubiquitin-specific peptidase 22 (USP22) is essential for HGF-induced melanoma metastasis. HGF treatment dramatically increased the expression of both USP22 and multiple integrin family members in particular ITGAV, ITGB3, and ITGA1. An unbiased analysis of the TCGA database reveals integrins as common downstream targets of both USP22 and HGF across multiple human cancer types. Notably, CRISPR-mediated deletion of USP22 completely eliminates HGF-induced integrin expression in melanoma cells. At the molecular level, USP22 acts as a bona fide deubiquitinase for Sp1, a transcription factor for the ITGAV, ITGB3, and ITGA1 genes. USP22 interacts with and inhibits Sp1 ubiquitination, protecting against Sp1 proteasomal degradation. Supporting this, immunohistology analysis detects a positive correlation among USP22, Sp1, and integrin αv in human melanoma tissues. This study identifies the death from the signature gene USP22 as a critical positive regulator for HGF-induced integrin expression by deubiquitinating the Sp1 transcription factor during melanoma metastasis.Copyright © 2024. Published by Elsevier B.V.