Expression Of Serine Protease HtrA3 In Gastric Cancer And Its Clinical Significance In Postoperative Patients With Gastric Cancer

Background and purposeNumerous studies have shown that the regulatory role of serine protease HtrA3 in tumorigenesis and development may be dual.That is,tumor suppressor or tumor promoter,depending on the specific tissue,the stage of tumor progression,etc.On the one hand,the expression of HtrA3 is reduced or even lost in endometrial cancer,ovarian cancer and non-small cell lung cancer.On the other hand,oral squamous cell carcinoma,thyroid cancer and colorectal cancer with high expression of HtrA3.Among them,HtrA3 is closely related to the acquisition of aggressive phenotypes and poor prognosis in oral squamous cell carcinoma and colorectal tumors.However,the expression of HtrA3 in gastric cancer(GC)is currently unclear,and the specific mechanism of HtrA3’s role in human tumors is still unclear.Therefore,in this study,we compared the expression of HtrA3 in GC and adjacent normal gastric mucosa tissues and evaluated the relationship between HtrA3 and clinicopathological characters,such as tumor differentiation,lymph node metastasis and other common clinical prognostic indicators.In addition,in order to predict the impact of HtrA3 on prognosis,we assessed the correlation between HtrA3 and overall survival(OS)and disease-free survival(DFS)in postoperative patients with gastric cancer.Furthermore,patients with GC were collected from TCGA and GTEx databases.We compared the expression of HtrA3 in GC and normal gastric mucosa tissues.What’s more,we explained the enrichmental pathways and functions of HtrA3 in GC through bioinformatics analysis softwares.Methods1.The paraffin-embedded tissue specimens of gastric cancer from 60 patients treated with gastrectomy were collected as the research object.The selected patients were all newly treated cases,and all had clear postoperative pathological types.According to the American Association of Cancer(AJCC)7th edition TNM staging standard.First,the selected paraffin-embedded tissue specimens were sectioned for HtrA3 immunohistochemical detection.2.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.Then,DEG analysis,GO analysis,GSEA analysis and other biometric methods were used to explain the enrichmental pathways and functions of HtrA3.Results1.The high expression rate of HtrA3 protein in gastric cancer tissues was 61.7%,higher than that in adjacent tissues at 16.7%(P<0.01).In 60 cases of gastric cancer specimens,the high expression of HtrA3 was significantly related to the depth of invasion(P=0.003),lymph node metastasis(P=0.002),and TNM staging(P=0.017),and the difference was statistically significant(P<0.05);Tumor location,degree of differentiation,HP infection,Her2 gene status,Ki-67 expression,intravascular tumor thrombosis and neurological invasion,tumor family history,smoking,gender and age are not related,and there is no statistical significance(P>0.05);Among the 60 gastric cancer specimens,there were 37 cases in the HtrA3 high expression group and 23 cases in the HtrA3 low expression group,univariate survival analysis showed that the median OS of gastric cancer patients with high and low expression of HtrA3 were 31.3 months and 46.2 months respectively[HR=1.73,P=0.025)],and the median DFS were 12.6 months and 14.6 months respectively [HR=1.49,P=0.038)];Cox hazard proportional regression model showed that depth of invasion of T3-4,positive lymph node metastasis,TNM stage Ⅲ,and High expression of HtrA3 were independent risk factors for the prognosis of patients after radical gastrectomy(P<0.05).2.Biological information analysis demonstrated that,Firstly,the pan-cancer analyses were performed to compare the expression of HtrA3 in the tumor samples of GTEx combined with TCGA and the corresponding normal samples of TCGA by Wilcoxon rank sum test.Secondly,we compared the expression of HtrA3 in 32 paracancerous samples and 375 GC samples in TCGA STAD dataset.The expression of HtrA3 was significantly high in GC samples(P=0.002).However,there was no significant difference in the expression of HTRA3 in 27 GC samples and matched paracancerous samples(P=0.117).ROC was used to analyze the distinguishing efficacy of HtrA3 between GC tissues and normal gastric mucosa tissue.The area under the curve(AUC)of HtrA3 is 0.710,suggesting that HtrA3 may be a potentially moderate identification molecule for GC tissues.In the end,GSEA showed that High HtrA3 expression may activate NF-k B pathway,YAP1/WWTR1/TAZ pathway,and TGF-β pathway.ConclusionThrough this study,we confirmed the positive expression rate of HtrA3 in gastric cancer tissues is significantly up-regulated,and is associated with the depth of invasion,tumor diameter,lymph node metastasis and TNM staging of gastric cancer,therefore it might be utilized as potential indicator for the prognosis of gastric cancer patients.