VMA21: unveiling a novel oncogene that facilitates immune evasion in triple-negative breast cancer through TCIRG1 protein stability regulation.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.