High SLC35C2 expression promotes proliferation and migration of hepatocellular carcinoma and is associated with immune infiltration and drug sensitivity: an analysis based on multi-omics database and in vitro functional verification

Hepatocellular carcinoma(HCC) is a complex disease with unpredictable prognosis. Identifying specific biomarkers can facilitate a better understanding of the pathogenesis of HCC and further improve its diagnosis, treatment, and prognostic assessment. This study aims to investigate the expression pattern, prognostic relevance, and immune infiltration correlation of solute carrier family 35 member C2(SLC35C2) in HCC based on multiple databases.

Multi-omics databases including TCGA, GTEx, GEO, HPA, CellMiner, and TCIA were integrated to assess the clinical value of SLC35C2, and an HCC risk prediction nomogram was constructed. Univariate and multivariate analyses were performed to identify clinical characteristics associated with overall survival in HCC patients(n=373). GO functional annotation, KEGG pathway enrichment, and gene set enrichment analysis(GSEA) were conducted to explore potential functional pathways. ESTIMATE was used to calculate tumor microenvironment scores, including stromal score, immune score and ESTIMATE score, and CIBERSORT was employed to evaluate the relative abundance of tumor-infiltrating immune cells. The predictive value of SLC35C2 for immunotherapy response and drug sensitivity was assessed through TCIA and CellMiner. CCK-8, Transwell and wound healing assays were applied to determine the effects of SLC35C2 overexpression on the cell proliferation and migration in human HCC cell line HepG2.

SLC35C2 was highly expressed in HCC(P<0.05), suggesting poor prognosis for patients. Multivariate Cox regression analysis on TCGA data indicated that high SLC35C2 expression was an independent risk factor for prognosis in HCC patients(P<0.05). Functional enrichment analyses indicated that SLC35C2 was closely associated with biological processes such as cell cycle, DNA replication, and Wnt signaling pathway(P<0.05). Immune-related analysis showed that in HCC tissues, the stromal score, immune score, and ESTIMATE score were significantly lower in the high-expression group of SLC35C2 than the low-expression group(all P<0.05). The immunophenotype score was negatively correlated with SLC35C2 expression level(P<0.05). SLC35C2 expression was associated with antitumor drug sensitivity, and its high expression indicated poor response to immunotherapy(P<0.05). Specifically, high SLC35C2 expression was positively correlated with the half-maximal inhibitory concentration (IC₅₀) of dabrafenib, R-1530, LDK-378, and methotrexate(P<0.05), and negatively correlated with the IC₅₀ of NU-6027, pomalidomide, I-BET-762, and PT-2385(P<0.05). In vitro experiments demonstrated that overexpression of SLC35C2 significantly enhanced the proliferation and migration of HepG2(P<0.05).

SLC35C2 is associated with abnormal immune infiltration in HCC, and its high expression indicates poor prognosis for HCC patients. Overexpression of SLC35C2 can enharce the migration and invasion of HCC cell line, suggesting that SLC35C2 may serve as a potential biomarker and target for the management and intervention of HCC.