Zhang Guangze, Qu Weilong, Huang Xinkun, Yi Jianfeng, Gao Hanxu, He Jiancheng, Xue Wanjiang
Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong, China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China; Nantong Key Laboratory of Gastrointestinal Oncology, Nantong, China.
Department of Gastrointestinal Surgery, Affiliated Hospital and Medical School of Nantong University, Nantong, China; Nantong Hospital of Traditional Chinese Medicine, Nantong, China.
Lab Invest. 2025 Feb;105(2):102202. doi: 10.1016/j.labinv.2024.102202. Epub 2024 Nov 28.
E3 ubiquitin ligases, crucial enzymes in the ubiquitination pathway, significantly influence the development of malignant tumors, including gastric cancer (GC), by regulating the stability of oncogenic and tumor-suppressive proteins. This study employed bioinformatics analysis of public databases alongside various experimental techniques-tissue arrays, real-time reverse-transcription polymerase chain reaction, western blot, immunofluorescence, and coimmunoprecipitation-to identify and explore the role of HECW1, a pivotal NEDD4 family E3 ubiquitin ligase, in GC progression. The results demonstrated that HECW1 is markedly overexpressed in GC tissues relative to normal gastric tissues, and its elevated expression correlates with poor prognosis in GC patients. In vitro experiments revealed that HECW1 overexpression significantly enhances the metastatic capabilities of GC cells. Mechanistically, HECW1 interacts with HIPK2 to facilitate its ubiquitination and degradation, thereby activating AKT and promoting the expression of downstream epithelial mesenchymal transition-related genes. In vivo experiments confirmed HECW1's role in promoting GC cell metastasis, highlighting the HECW1-HIPK2-AKT signaling axis as critical in GC metastasis. These findings not only elucidate a novel metastasis mechanism of GC but also suggest potential molecular targets for developing new therapeutic strategies against GC.
E3泛素连接酶是泛素化途径中的关键酶，通过调节致癌蛋白和抑癌蛋白的稳定性，对包括胃癌（GC）在内的恶性肿瘤的发展产生重大影响。本研究利用公共数据库的生物信息学分析以及各种实验技术——组织芯片、实时逆转录聚合酶链反应、蛋白质免疫印迹、免疫荧光和免疫共沉淀——来识别和探索关键的NEDD4家族E3泛素连接酶HECW1在胃癌进展中的作用。结果表明，相对于正常胃组织，HECW1在GC组织中明显过表达，其表达升高与GC患者的不良预后相关。体外实验表明，HECW1过表达显著增强了GC细胞的转移能力。从机制上讲，HECW1与HIPK2相互作用，促进其泛素化和降解，从而激活AKT并促进下游上皮-间质转化相关基因的表达。体内实验证实了HECW1在促进GC细胞转移中的作用，突出了HECW1-HIPK2-AKT信号轴在GC转移中的关键作用。这些发现不仅阐明了GC的一种新的转移机制，还为开发针对GC的新治疗策略提供了潜在的分子靶点。
