Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, China; No. 1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China.
Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, China; Department of Chinese Medicine, Changshu No.2 People's Hospital, Changshu, 215500, Jiangsu, China.
Pharmacol Res. 2023 Feb;188:106644. doi: 10.1016/j.phrs.2022.106644. Epub 2023 Jan 2.
poorly cohesive (PC) gastric cancer (GC) (PC-GC) is a distinct histological subtype of GC and is defined as a tumor consisting of isolated or small clusters of tumor cells with poorly differentiated and metastatic characteristics. According to multiple studies, PC-GC is intrinsically heterogeneous, with mesenchymal variants being the most aggressive. However, to date, the molecular mechanisms associated with PC-GC are still not fully understood. This study investigated the role of the USP51/ZEB1/ACTA2 axis in promoting GC metastasis. Single-cell sequencing revealed that E-box binding homeobox 1 (ZEB1) expression was significantly increased in a subpopulation of low-adherent cells and was an independent prognostic factor in GC patients. Furthermore, the bulk transcriptome analysis revealed a significant positive correlation between Ubiquitin Specific Peptidase 51 (USP51), ZEB1, and Actin Alpha 2 (ACTA2), and our data further confirmed that all three were highly co-localized in PC-GC tissues. According to the findings of in vitro and in vivo experiments, USP51 was able to maintain ZEB1 expression to promote ACTA2 transcription, thereby activating the mesenchymal phenotype of GC cells and promoting tumor metastasis. Moreover, USP51 could recruit and activate stromal cells, including M2-like macrophages and fibroblasts, through cancer cells. Clinical data suggested that overexpression of USP51 predicts that patients have difficulty benefiting from immunotherapy and is associated with immune-exclusion tumor characteristics. Collectively, the findings of this study shed light on a key mechanism by which elevated USP51 expression induces Epithelial-mesenchymal transition (EMT) in GC cells, hence facilitating GC cell proliferation, survival, and dissemination. In this view, USP51/ZEB1/ACTA2 may serve as a candidate therapeutic target against GC metastasis.
低黏附性（PC）胃癌（GC）（PC-GC）是 GC 的一种独特组织学亚型，定义为由孤立或小簇肿瘤细胞组成的肿瘤，这些细胞具有低分化和转移性特征。根据多项研究，PC-GC 本质上是异质的，其中间质变体最为侵袭性。然而，迄今为止，与 PC-GC 相关的分子机制仍未完全阐明。本研究探讨了 USP51/ZEB1/ACTA2 轴在促进 GC 转移中的作用。单细胞测序显示，E-盒结合同源盒 1（ZEB1）在低黏附细胞的一个亚群中的表达显著增加，并且是 GC 患者的独立预后因素。此外，大量转录组分析显示，泛素特异性肽酶 51（USP51）、ZEB1 和肌动蛋白α 2（ACTA2）之间存在显著的正相关，并且我们的数据进一步证实，这三者在 PC-GC 组织中高度共定位。根据体外和体内实验的结果，USP51 能够维持 ZEB1 的表达以促进 ACTA2 的转录，从而激活 GC 细胞的间质表型并促进肿瘤转移。此外，USP51 可以通过癌细胞招募和激活基质细胞，包括 M2 样巨噬细胞和成纤维细胞。临床数据表明，USP51 的过表达预示着患者难以从免疫治疗中获益，并与免疫排斥肿瘤特征相关。总之，本研究的结果揭示了 USP51 表达升高诱导 GC 细胞上皮-间质转化（EMT）的关键机制，从而促进 GC 细胞的增殖、存活和扩散。在这种观点下，USP51/ZEB1/ACTA2 可能成为针对 GC 转移的候选治疗靶点。
