DataSheet_1_HTRA3 Is a Prognostic Biomarker and Associated With Immune Infiltrates in Gastric Cancer.zip

HtrA serine peptidase 3 (HTRA3) participates in multiple signal pathways and plays an important regulatory role in various malignancies; however, its role on prognosis and immune infiltrates in gastric cancer (GC) remains unclear. The study investigated HTRA3 expression in tumor tissues and its association with immune infiltrates, and determined its prognostic roles in GC patients. Patients with GC were collected from the cancer genome atlas (TCGA). We compared the expression of HTRA3 in GC and normal gastric mucosa tissues with Wilcoxon rank sum test. And logistic regression was used to evaluate the relationship between HTRA3 and clinicopathological characters. Gene ontology (GO) term analysis, Gene set enrichment analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA) was conducted to explain the enrichmental pathways and functions and quantify the extent of immune cells infiltration for HTRA3. Kaplan-Meier analysis and Cox regression were performed to evaluate the correlation between HTRA3 and survival rates. A nomogram, based on Cox multivariate analysis, was used to predict the impact of HTRA3 on prognosis. High HTRA3 expression was significantly correlated with tumor histological type, histological grade, clinical stage, T stage, and TP53 status (P < 0.05). HTRA3-high GC patients had a lower 10-year progression-free interval [PFI; hazard ratio (HR): 1.46; 95% confidence interval (CI): 1.02–2.08; P = 0.038], disease-specific survival (DSS; HR: 1.65; CI: 1.08–2.52; P = 0.021) and overall survival (OS; HR: 1.59; CI: 1.14–2.22; P = 0.006). Multivariate survival analysis showed that HTRA3 was an independent prognostic marker for PFI (HR: 1.456; CI: 1.021–2.078; P = 0.038), DSS (HR: 1.650; CI: 1.079–2.522; P = 0.021) and OS [hazard ratio (HR): 1.590; 95% confidence interval (CI):1.140–2.219; P = 0.006]. The C-indexes and calibration plots of the nomogram based on multivariate analysis indicated an effective predictive performance for GC patients. GSEA showed that High HTRA3 expression may activate NF-κB pathway, YAP1/WWTR1/TAZ pathway, and TGFβ pathway. There was a negative correlation between the HTRA3 expression and the abundances of adaptive immunocytes (T helper cell 17 cells) and a positive correlation with abundances of innate immunocytes (natural killer cells, macrophages etc.). HTRA3 plays a vital role in GC progression and prognosis and could be a moderate biomarker for prediction for survival after gastrectomy.

HtrA丝氨酸肽酶3（HTRA3）参与多种信号通路，并在多种恶性肿瘤中发挥重要的调控作用；然而，其在胃癌（GC）预后和免疫浸润方面的作用尚不明确。本研究探讨了HTRA3在肿瘤组织中的表达及其与免疫浸润的相关性，并确定了其在GC患者预后中的作用。研究者从癌症基因组图谱（TCGA）中收集了GC患者。通过Wilcoxon秩和检验比较了GC和正常胃黏膜组织中HTRA3的表达。采用逻辑回归评估了HTRA3与临床病理特征之间的关系。通过基因本体（GO）术语分析、基因集富集分析（GSEA）和单样本基因集富集分析（ssGSEA）来解释富集途径和功能，并量化HTRA3免疫细胞浸润的程度。Kaplan-Meier分析和Cox回归用于评估HTRA3与生存率之间的相关性。基于Cox多变量分析的评分图被用于预测HTRA3对预后的影响。高HTRA3表达与肿瘤组织学类型、组织学分级、临床分期、T分期和TP53状态显著相关（P < 0.05）。高HTRA3表达的GC患者具有较低的10年无进展生存期[无进展生存期（PFI）；风险比（HR）：1.46；95%置信区间（CI）：1.02–2.08；P = 0.038]，疾病特异性生存期（DSS；HR：1.65；CI：1.08–2.52；P = 0.021）和总生存期（OS；HR：1.59；CI：1.14–2.22；P = 0.006）。多变量生存分析显示，HTRA3是PFI（HR：1.456；CI：1.021–2.078；P = 0.038）、DSS（HR：1.650；CI：1.079–2.522；P = 0.021）和OS[风险比（HR）：1.590；95%置信区间（CI）：1.140–2.219；P = 0.006]的独立预后标志物。基于多变量分析的评分图的C指数和校准图表明，对GC患者具有有效的预测性能。GSEA显示，高HTRA3表达可能激活NF-κB通路、YAP1/WWTR1/TAZ通路和TGFβ通路。HTRA3的表达与适应性免疫细胞（T辅助细胞17细胞）的丰度呈负相关，与先天免疫细胞（自然杀伤细胞、巨噬细胞等）的丰度呈正相关。HTRA3在GC的进展和预后中起着至关重要的作用，并可能成为预测胃切除术后的生存率的适度生物标志物。