Qi Liu, Yuyang Liu, Junyi Chen, Tao Wan, Chao Li, Zhanyu Yang, Ning Zhang
Liver hepatocellular carcinoma (LIHC) is a molecularly heterogeneous malignancy for which additional genetically supported biomarkers and functional regulators remain to be identified. We aimed to identify candidate genes through integrative genetic and transcriptomic screening, then determine the cellular context and functional relevance of the leading candidate. We applied Summary-data-based Mendelian Randomization to FinnGen LIHC genome-wide association summary statistics and GTEx v8 liver cis-eQTL summary data. A 1000 Genomes European-ancestry panel provided the linkage disequilibrium reference. Candidate genes were cross-referenced with Gene Expression Omnibus differentially expressed genes and TCGA-LIHC prognostic genes. After ATP13A2 emerged from this screen, we used bulk, single-cell, and spatial transcriptomic analyses to characterize its expression and cellular context. HUVEC knockdown, migration, tube formation, qRT-PCR, and Western blotting were then used for functional assessment. ATP13A2 was the only gene shared by the SMR-prioritized, GEO differential-expression, and TCGA-LIHC prognostic sets. ATP13A2 expression was higher in LIHC tissues and independently associated with worse survival in the TCGA-LIHC cohort. Single-cell analysis subsequently localized ATP13A2 predominantly to tumor endothelial cells, and spatial and pathway analyses associated ATP13A2-positive endothelial cells with angiogenic programs and inferred PTN-NCL signaling. In HUVECs, ATP13A2 knockdown reduced migration and tube formation and was accompanied by reduced ERK1/2 and p38 MAPK phosphorylation. An unbiased integrative screen prioritized ATP13A2 as a genetically supported LIHC candidate, after which single-cell analysis identified its tumor-endothelial context. Functional knockdown data support an association with endothelial angiogenic phenotypes. Rescue, in vivo, and independent clinical validation remain required.