Guo Xiangyang, Chen Zhiqiang, Miao Yongmin, Zhang Guochen, Miao Lifeng
Department of Breast Surgery, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University Taiyuan 030013, Shanxi, P. R. China.
Am J Cancer Res. 2024 Aug 25;14(8):4096-4111. doi: 10.62347/NGSD3193. eCollection 2024.
VMA21 has been shown to be dysregulated in a number of cancers. However, no study has yet explored whether VMA21 is involved in the regulation of triple-negative breast cancer (TNBC), especially from the level of immune escape.
The Gene Expression Omnibus (GEO) database was accessed to obtain the microarray dataset identified as GSE38959, which was then subjected to an analysis aimed at identifying genes that are differentially expressed (DEGs). The researchers examined the expression of VMA21 in TNBC cell lines. After knockdown of VMA21 in TNBC cells, cell proliferation, invasion, and migration were assessed by clone formation, cell scratch, and Transwell assay, respectively. The effect of VMA21 on immune cell function was explored by cell co-culture method, which was used to assess how TNBC cells with suppressed VMA21 expression affected CD8+ T cytotoxic potential and cytokine secretion. The effect of VMA21 on TCIRG1 protein stability and ubiquitination was assessed using immunoprecipitation. The effects of VMA21 knockdown on tumor xenograft growth and CD8+ T cell immune infiltration in mice were further evaluated.
VMA21 expression is significantly elevated across various cell lines of TNBC. Furthermore, the perturbation of VMA21 notably suppresses key cell viability parameters in TNBC cells, including their proliferation, invasiveness, and migratory abilities. The modulation of VMA21 in TNBC cells can lead to a substantial augmentation in CD8+ T cell effectiveness. VMA21 stabilizes TCIRG1 protein expression by inhibiting its ubiquitination degradation. Further, VMA21 is involved in regulating TNBC cell proliferation, invasion and immune escape by promoting TCIRG1 expression.
VMA21 is able to regulate TCIRG1 protein stability by binding to TCIRG1 protein in the form of ubiquitination, which ultimately promotes the malignant behavior as well as immune escape of TNBC cells.
已证明VMA21在多种癌症中表达失调。然而，尚无研究探讨VMA21是否参与三阴性乳腺癌（TNBC）的调控，尤其是从免疫逃逸层面。
访问基因表达综合数据库（GEO）以获取标识为GSE38959的微阵列数据集，随后对其进行分析以鉴定差异表达基因（DEG）。研究人员检测了TNBC细胞系中VMA21的表达。在TNBC细胞中敲低VMA21后，分别通过克隆形成、细胞划痕和Transwell实验评估细胞增殖、侵袭和迁移能力。通过细胞共培养方法探究VMA21对免疫细胞功能的影响，该方法用于评估VMA21表达受抑制的TNBC细胞如何影响CD8 + T细胞的细胞毒性潜能和细胞因子分泌。使用免疫沉淀法评估VMA21对TCIRG1蛋白稳定性和泛素化的影响。进一步评估敲低VMA21对小鼠肿瘤异种移植生长和CD8 + T细胞免疫浸润的影响。
VMA21在TNBC的各种细胞系中表达显著升高。此外，VMA21的扰动显著抑制TNBC细胞的关键细胞活力参数，包括其增殖、侵袭和迁移能力。TNBC细胞中VMA21的调节可导致CD8 + T细胞有效性的大幅增强。VMA21通过抑制其泛素化降解来稳定TCIRG1蛋白表达。此外，VMA21通过促进TCIRG1表达参与调节TNBC细胞增殖、侵袭和免疫逃逸。
VMA21能够通过以泛素化形式与TCIRG1蛋白结合来调节TCIRG1蛋白稳定性，最终促进TNBC细胞的恶性行为以及免疫逃逸。
