MAPK-RAP1A Signaling Enriched in Hepatocellular Carcinoma Is Associated With Favorable Tumor-Infiltrating Immune Cells and Clinical Prognosis

Abstract

Background: MAPK-RAP1A signaling, which is involved in cancer progression, remains to be defined. Upregulation of MAPK-RAP1A signaling accounts for most cancers that harbor high incident rate, such as non-small cell lung cancer (NSCLC) and pancreatic cancer, especially in hepatocellular carcinoma (HCC). MAPK-RAP1A signaling plays an important function as clinical diagnosis and prognostic value in cancers, and the role of MAPK-RAP1A signaling related with immune infiltration for HCC should be elucidated.

Methods: Microarray data and patient cohort information from The Cancer Genome Atlas (TCGA; n = 425) and International Cancer Genome Consortium (ICGC; n = 405) were selected for validation. The Cox regression and least absolute shrinkage and selection operator (LASSO) were used to construct a clinical prognostic model in this analysis and validation study. We also tested the area under the curve (AUC) of the risk signature that could reflect the status of predictive power by determining model. MAPK-RAP1A signaling is also associated with tumor-infiltrating immune cells (TICs) as well as clinical parameters in HCC. The GSEA and CIBERSORT were used to calculate the proportion of TICs, which should be beneficial for the clinical characteristics (clinical stage, distant metastasis) and positively correlated with the survival of HCC patients.

Results: HCC patients with enrichment of MAPK-RAP1A signaling were associated with clinical characteristics and favorable T cell gamma delta (Vδ T cells), and STMN1, RAP1A, FLT3, HSPA8, ANGPT2, and PGF were used as candidate biomarkers for risk scores of HCC. To determine the molecular mechanism of this signature gene association, Gene Set Enrichment Analysis (GSEA) was proposed. Cytokine-cytokine receptor interaction, TGF-β signaling pathway, and Intestinal immune network for IgA production gene sets were closely related in MAPK-RAP1A gene sets. Thus, we established a novel prognostic prediction of HCC to deepen learning of MAPK-RAP1A signaling pathways.

Conclusion: Our findings demonstrated that HCC patients with enrichment of MAPK-RAP1A signaling were associated with clinical characteristics and favorable T cell gamma delta (Vδ T cells), which may be a novel prognostic prediction of HCC.

Keywords: MAPK-RAP1A signaling; gamma delta T cell; hepatocellular carcinoma; prognosis; tumor-infiltrating immune cells.