NCAPD2 Modulates MHC-I Antigen Presentation via the PI3K/AKT Axis to Drive Metastatic Progression in Gastric Cancer.

Abstract

Background: Impaired major histocompatibility complex class I (MHC-I) antigen presentation constitutes a fundamental mechanism of tumor immune evasion, yet the upstream molecular drivers in gastric cancer (GC) remain enigmatic. Although non-structural maintenance of chromosomes condensin I complex subunit D2 (NCAPD2) demonstrates oncogenic potential across malignancies, its functional crosstalk with immune surveillance mechanisms remains unexplored.

Methods: We conducted transcriptome sequencing on NCAPD2-silenced GC cell lines to identify differentially expressed genes (DEGs), followed by GO and KEGG pathway analyses. Leveraging the TCGA cohort, we analyzed NCAPD2 expression patterns and evaluated its clinical relevance in GC through survival analysis. Orthogonal validation was performed via qRT-PCR and Western blot to quantify mRNA and protein levels of NCAPD2 and MHC-I. To functionally characterize the oncogenic phenotype, we employed CCK-8, wound healing, Transwell, and flow cytometry, providing a multi-parametric assessment of malignant progression mechanisms.

Results: NCAPD2 was overexpressed in GC tissues and associated with poorer patient survival. Functional characterization in GC cell lines revealed that NCAPD2 knockdown significantly inhibited malignant phenotypes, including slowed proliferation, weakened migration, reduced invasion, and enhanced apoptosis. Mechanistically, NCAPD2 downregulated MHC-I surface expression, a critical immune evasion mechanism, and this suppression was partially rescued by treatment with the PI3K inhibitor LY294002, suggesting the involvement of the PI3K/Akt signaling pathway in NCAPD2-mediated immune escape.

Conclusion: In GC, elevated NCAPD2 expression is a negative prognostic marker associated with advanced tumor stage and poorer survival. Functionally, NCAPD2 promotes malignant phenotypes and downregulates MHC-I antigen presentation via the PI3K/AKT pathway, thereby facilitating immune evasion. These findings suggest NCAPD2 as a potential therapeutic target in GC.