| Gastric cancer(GC)is one of the most common malignant tumors worldwide and causes a major health problem due to its high incidence rate,invasion and metastasis,prominent clinical symptom,and low cure rate.Gastric cancer is listed as the top 5 malignant tumor in the world from the aspect of incidence.These data demonstrate that gastric cancer seriously threatens human health and obstructs the economic and social development.Currently,the main treatment for gastric cancer is surgical resection and postoperative 5-year survival rate for early-stage gastric cancer patients is more than 90%.However,most patients with gastric cancer are at the advanced stage when diagnosed andhas lost the chance of radical surgery,making the 5-year survival rates of 11-40%only.Therefore,an important and urgent issue in current gastric cancer research is to improve the early diagnosis rate of gastric cancer and to discover novel molecμlar targeted drugs and predictive biomarkers for the metastasis and recurrence of gastric cancer.Recent studies demonstrate that a multi-subunit vacuolar H+-ATPase(V-ATPase)is closely associated with the invasion and metastasis of gastric cancer.Here we investigated the expression and role of the human ATP6V1A gene that encodes the catalytic subunit A of V-ATPase in GC.We found that ATP6V1A expression level is significantly elevated in GCs compared to normal tissues,but GC patients with higher expression levels of ATP6VIA have a better prognosis.Genomic analysis revealed that APT6V1A copy number is gained in a small fraction of GC patients and lost in a minimum number.Moreover,the ATP6V1A copy number was positively correlated with its mRNA level.To explore additional mechanisms by which ATP6V1A overexpressed in GCs,we investigated the relationship between transcription factor YY1 and ATP6V1A,and found that mRNA expression of YY1 had significant correlation with that of ATP6V1A.To validate that YY1 transcriptionally regμlates ATP6V1A,we discovered that the ATP6V1A core promoter region contains three YY1 binding sites.Moreover,RNAi-mediated knockdown of YY1 in GC cells significantly decreased ATP6V1A mRNA and protein expression,while YY1 overexpression increased ATP6V1A expression level.A series of experiments confirm that YY1 interacts with ATP6V1A core promoter region.In conclusion,YY1 may play an important regμlatory role in ATP6V1A expression with potential mechanistic and clinical implications in GC and higher expression level of ATP6V1A favors a good prognosis in gastric cancer.Analysis of gene expression patterns in GC can help to identify a comprehensive panel of gene biomarkers for predicting clinical outcomes and to discover potential new therapeutic targets.To establish a novel prognostic scoring system for GC,a multi-step bioinformatics analytic approach was developed.We first identified 276 genes that were robustly differentially expressed between normal and GC tissues,of which,249 were found to be significantly associated with overall survival(OS)by univariate Cox regression analysis.The biological functions of 249 genes are related to cell cycle,RNA/ncRNAprocess,acetylation and extracellular matrix organization.A network was generated for view of the gene expression architecture of 249 genes in 265 GCs.Finally,we applied a canonical discriminant analysis approach to identify a 53-gene signature and a prognostic scoring system was established based on a canonical discriminant function of 53 genes.The prognostic scores strongly predicted patients with GC to have either a poor or good OS.Our study raises the prospect that the practicality of GC patient prognosis can be assessed by this prognostic scoring system to reach the goal of precision medicine forgastric cancer. |
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