Significance And Relationship Between The Expression Of YAP And Survivin In Gastric Carcinoma And Precancerous Lesions

ObjectiveWe detected the expression of YAP and Survivin in normal gastric mucosa, intestinal metaplasia,atypical hyperplasia and gastric carcinoma,to analyse the differences and relevance of the two,and to explore the correlation and significance of the expression of YAP and Survivin in gastric carcinoma and precancerous lesions.MethodsClinical data and tisue microarray construction:Surgically resected specimens of 103 cases of gastric carcinoma and paired normal gastric mucosa(≥5cm away from the edge of the tumor),71 cases of intestinal metaplasia,40 cases of atypical hyperplasia,31 cases of early gastric carcinoma and 72 cases of advanced gastric carcinoma were collected from No.1 Hospital of China Medical University.Tissue microarrays including gastric carcinomas and precancerous lesions were constructed using Microarrayer,4μm consecutive sections were cut,one performed conventional HE staining,others were stored at room temperature for further immunohistochemical staining.Immunohistochemical method and assessment:Envision immunohistochemical method was used to detect the expression of YAP and Survivin in normal gastric mucosa,intestinal metaplasia,atypical hyperplasia and gastric carcinoma,rabbit anti-human YAP polyclonal antibody(work dilution 1:25)was purchased from the Cell Signaling Technology Company,rabbit anti-human Survivin polyclonal antibody (ready to use) was from Maixim biological Company.Known positive tissue section was used as positive control,with PBS instead of primary antibodies as a negative control.Immunohistochemical staining results assement:YAP positive reaction was defined as clearly brown granules located in nuclear and/or cytoplasm,Survivin positive reaction was defined as clearly brown granules located in cytoplasm.For each case,select 2 represented areas,200 cells were counted in high-power visual field. Staining intensity of positive cells was assessed into four grades:0,negative;1,light brown;2,brown;3,dark brown.Then staining on the percentage of positive cells:0,no positive cells;1,positive cells≤25%;2,positive cells 26-50%;3,positive cells 51-75%;4,positive cells≥76%.According to the product scores the results were divided into four grades-(0),+(1-4),++(5-8),+++(9-12).ResultsRemoving the shedding of some tissues during antigen retrieval,finally available samples were 98 cases of normal gastric mucosa,58 cases of intestinal metaplasia,32 cases of atypical hyperplasia,29 cases of early gastric carcinoma,69 cases of advanced gastric carcioma.YAP located in the nuclear and/or cytoplasm,Survivin located in the cytoplasm.The positive rates of YAP in atypical hyperplasia(12/32,37.5%) and gastric carcinoma(47/98,48.0%)were significantly higher than that in normal gastric mucosa (13/98,13.3%),P＜0.01;There was no statistical difference between YAP expressions in the normal gastric mucosa and intestinal metaplasia(16/58,27.6%),atypical hyperplasia and gastric carcinoma,P＞0.05;The expressive level showed an increased trend from high-differentiated tubular adenocarcinoma(4/12,33.3%),moderately-differentiated tubular adenocarcinoma(11/25,44.0%) to poorly-differentiated tubular adenocarcinoma(24/41,58.5%),although,without significant Rank correlation;In Lauren's types of gastric carcinoma,the positive rate of YAP in diffused gastric carcinoma(31/59,52.5%) also showed increased trend compared with that in intestinal gastric carcinoma(16/39,41.0%) but with no statistical significance,P＞0.05.The positive rate of YAP expression showed an increased inclination from gastric carcinoma with lymph node metastasis(24/52,46.2%) to the group without lymph node metastasis (5/17,29.4%),though without statistical significance,P＞0.05.There was no significant correlation of the expression of YAP with patients' gender,age and Borrmann's classification of gastric carcinoma,P＞0.05.The positive rates of Survivin in intestinal metaplasia(31/58,53.4%),atypical hyperplasia(19/32,59.4%) and gastric carcinoma(64/98,65.3%) were significantly higher than that in normal gastric mucosa(11/98,11.2%),P＜0.01;There was no significant difference between intestinal metaplasia and atypical hyperplasia,atypical hyperplasia and gastric carcinoma,P＞0.05.The expressive level was gradually increasing from high-differentiated tubular adenocarcinoma(5/12,41.7%), moderately-differentiated tubular adenocarcinoma(14/25,58.3%) to poorly-differentiated tubular adenocarcinoma(31/41,75.6%),and had significant Rank correlation,r_k=0.279,P＜0.01;In Lauren's types of gastric carcinoma,the positive rate of Survivin in gastric carcinoma of diffuse type(44/59,74.6%) is higher than that in intestinal type(20/39,51.3%),with statistical significance,P＜0.05.In gastric carcinoma with lymph node metastasis(40/52,76.9%),the positive rate of Survivin was significantly higher than that in the group without lymph node metastasis(7/17,41.2%), P＜0.01.There was no significant correlation between the expression of Survivin and patients' gender,age and Borrmann's classification of gastric carcinoma,P＞0.05.In 98 cases of gastric carcinoma,the expression of YAP and Survivin was positively correlated,r_k=0.246,P＜0.01.ConclusionsThe positive rates of YAP in atypical hyperplasia and gastric carcinoma were significantly higher than that in normal gastric mucosa,suggesting that YAP may play an important role as a carcinogenic factor and early gastric carcinogenic molecule during gastric carcinogenesis;There was no statistical difference between normal gastric mucosa and intestinal metaplasia,atypical hyperplasia and gastric carcinoma; The expressive level showed an increased trend from high-differentiated tubular adenocarcinoma,moderately-differentiated tubular adenocarcinoma to poorly-differentiated tubular adenocarcinoma,though had no statistical difference;In gastric carcinoma with lymph node metastasis,the positive rate of YAP also showed increased trend than that in the group without lymph node metastasis,though had no statistical significance.Whether the expression of YAP play roles in the cancerous cellular differention and lymph node metastasis needs further study.The positive rates of Survivin in intestinal metaplasia,atypical hyperplasia and gastric carcinoma were significantly higher than that in normal gastric mucosa;from well differentiated adenocarcinoma,moderately differentiated adenocarcinoma to poorly differentiated adenocarcinoma,the positive rate of Survivin gradually increased, that had significant Rank correlation.There was statistical significance of Survivin expression between intestinal type gastric carcinoma and diffused type gastric carcinoma;In gastric carcinoma with lymph node metastasis,the positive rate of Survivin was significantly higher than that in the group without lymph node metastasis, suggesting that Survivin may be involved in the occurrence,development and metastasis of gastric carcinoma.The expression of YAP and Survivin in 98 cases of gastric carcinoma was correlated.YAP may induce the expression of Survivin,which may participate in gastric carcinogenesis,development and metastasis by inhibiting apoptosis of gastric carcinoma and regulating cellular mitosis.Detecting the two markers together may help in early diagnosis of gastric carcinoma.