Integrated bulk and scRNA sequence identified anoikis-related diagnostic biomarkers and potential association with immune infiltration in type A aortic dissection

Abstract

Type-A aortic dissection (TAAD) is common life-threatening cardiovascular diseases with high-morbidity and mortality but the concrete etiology of disease remains unclear, which might disturb or delay the early diagnosis for TAAD. Anoikis is a special form of programmed cell-death (PCD) induced by detachment of anchorage-dependent cells from the extracellular matrix (ECM) or neighboring cells, and has been widely applied to identify anoikis-related biomarkers for the prediction and prognosis in oncological fields. However, the specific roles of anoikis-related genes (ARGs) in TAAD remain unclear. In this study, we first identified and validated eight diagnostic ARGs for TAAD based on multiple RNA-sequence datasets, including CHEK2, HIF1A, HK2, HMGA1, SERPINA1, PTPN1, SLC2A1 and VEGFA. The comprehensive functional annotation was evaluated by the integrated functional enrichments analysis. We identified the activation of inflammatory-related pathways, metabolic reprogramming and angiogenesis, and the inhibition of cardiovascular development pathways in TAAD. Immune cell infiltration (ICI) analysis further demonstrated that innate immune-cells were more dominant than adaptive immune-cells in TAAD tissues, especially in macrophages, monocytes, activated-DC, NKT cells and CD56+dim NK cells. The cellular landscape was further validated by single-cell RNA sequence technology with significant associations with anoikis in TAAD patients. Four vital ARGs (HIF1A, HMGA1, SERPINA1 and VEGFA) were ultimately identified along with the changes of differentiation trajectory, and major expressions were conformably concentrated on Macro1-3, Mono1-2 and Mono4 subtypes. These findings provide a promising diagnostic biomarker for the accurately diagnosing the disease and would be helpful to further explore the potential pathogenesis with anoikis process for TAAD.