The Expression Of Antiapoptosis Gene, Survivin And Its Roles In Gastrointestinal Stromal Tumor

Background and objectiveGastrointestinal stromal tumor(GIST) is the most frequent mesenchymal tumor of the gastrointestinal tract, the actual cell of origin of GIST is a pluripotential mesenchymal stem cell programmed to differentiate into the interstitial cell of Cajal. A great majority of GISTs occur in the GI-tract, omentum and mesentery. GIST specifically expresses C-KIT, it has poor prognosis and lacks of specific indicator in evaluating the malignant potential. So, it is important for the therapy and evaluation of malignant potential to find reliabale indicators and mechanism of infiltration and metabasis in GIST.Apoptosis is important to the stability of the internal environment of the body. The chaos of the regulation of apoptosis contributes to cell proliferation and the development of tumors, which is one of important mechanisms in the forming of the tumor. Survivin is a new member of IAP(inhibitors of apoptosis protein) family, which was identified by hybridization screening of a human P1 genomic library with the cDNA of EPR-1. Survivin has potential anti-apoptotic activities. In contrast to other IAP proteins, survivin was observed to be expressed in fetal tissues and most common human cancers, including carcinomas of the lung, stomach, colon, breast and prostate as well as high-grade non-Hodgkin's lymphomas, whereas no survivin transcripts were detected in normal, terminally differentiated adult tissues(except thymus gland and genital gland). It has been known that the overexpressed of survivin in tumor tissues is correlated with poor prognosis of the patients. The studies of recent years discovered that the expression of survivin has a relationship with tumor angiogenesis, and also found that there may be close links among expression of survivin and VEGF, bFGF in tumor angiogenesis.At present, the research on the expression of survivin in GIST and its relationship with the clinical pathologic characteristics has not yet reported, and the study on the relationship between survivin expression and angiogenesis, survivin expression and cell apoptosis in GIST is not clear. So we investigate not only the expression of survivin and its clinical significance but also the relationship among expression of survivin, angiogenesis, VEGF, bFGF and cell apoptosis in GIST, so as to provide a potentially new way for the therapy and evaluation of malignant potential of GIST.Materials and MethodsMaterials57 Gastrointestinal stromal tumor samples during April 2004 to March 2007 were collected in surgery and gastro-endoscope room, First Affiliated Hospital of Third Military Medical University. There were 30 male, 27 female patients and 40 in stomach, 13 in small intestine, 4 in rectum with initial occurring position. They were classified 12 VLR, 17 LR, 14 IR and 14 HR in malignant potential. No cases were received radiotherapy and chemiotherapy.Methods1. HE staining was used to detect all the 57 samples to verify the pathological diagnose.2. Used in situ hybridization(ISH) to detect the expression of survivin mRNA in 57 cases of GIST, and analyze the relationship between survivin expression and malignant potential, clinical pathologic characteristics of GIST.3. Used immunohistochemically staining to determine the expression of survivin, VEGF, bFGF and CD31 protein in 57 cases of GIST, the vascular endothelial cells were marked by CD31, and CD31was taken as the marker to calculate the microvessel density. Detect the correlation among survivin, VEGF, bFGF and MVD.4. Tdt-mediated dUTP nick and labeling(TUNEL) method was used to detect cell apoptosis in 57 cases of GIST, and analyze the relationship between survivin expression and cell apoptosis.Results1. The positive incidences of survivin mRNA expression in GIST was 71.9%. The expression of survivin mRNA was correlated with the malignant potential of GIST, and also correlated with infiltration and metabasis,tumor diameter and central necrosis of GIST, but was not correlated with patient's age, patient's sex and initial occurring position.2. The positive incidences of survivin expression in GIST was 66.7%. The expression of survivin was not only correlated with the malignant potential of GIST, but also correlated with infiltration and metabasis,tumor diameter and central necrosis of GIST.3. The positive incidences of VEGF expression in GIST was 73.7%, and the positive incidences of bFGF expression was 52.6%. The expression of VEGF and MVD were both correlated with the malignant potential of GIST, while the expression of bFGF was not correlated with the malignant potential of GIST. MVD was also correlated with infiltration and metabasis,tumor diameter and central necrosis of GIST.4. There was a positive correlation between the expression of survivin and VEGF, and also between survivin and bFGF. There was remarkable significance in comparison of MVD between positive survivin expression group and negative survivin expression group, and also between positive VEGF, bFGF expression groups and negative ones respectively.5. There was remarkable significance in comparison of AI between positive survivin mRNA expression group and negative survivin mRNA expression group, and also between positive survivin expression group and negative survivin expression group.DiscussionSurvivin gene was found it was the strongest apoptosis inhibitor, and was one of the important members of IAP family. Because of its unique structure, distribution and significant antiapoptosis, survivin gene has increasingly caught the attention of researchers. It was found in recent years that the expression of survivin gene was not only correlated with the tumor angiogenesis, but also with VEGF,bFGF.It was well known that angiogenesis, as a basic incidence, participates in many pathological processes including wound healing, chronic inflammation and tumors etc. Angiogenesis was involved in the whole process of the tumor infiltration and metabasis and play an important role in it. Vascular endothelial growth factor and basic fibroblast growth factor were both necessary factors that could promote angiogenesis. We investigate not only the expression of survivin and its clinical significance but also the relationship among expression of survivin, angiogenesis, VEGF, bFGF and cell apoptosis in GIST.We found that there was a clear correlation between survivin expression and the malignant potential of GIST not only in mRNA level, but also in protein level. Survivin expression was also correlated with infiltration and metabasis, tumor diameter and central necrosis of GIST. There was a positive correlation between the expression of survivin and VEGF, and also between survivin and bFGF, and survivin participated in angiogenesis of GIST. Moreover, survivin inhibited the apoptosis of GIST. Our research showed that survivin might become a indicator for evaluating the malignant potential of GIST, it could inhibit cell apoptosis, and it was probably involved in angiogenesis cooperatively with VEGF and bFGF in GIST, and they promote the malignant process of GIST together. We hope that it would provide some new evidence for the research of survivin function, evaluation of malignant potential and therapy of GIST.Conclusion1. There is a clear correlation not only between survivin mRNA expression and the malignant potential of GIST, but also between survivin expression and the malignant potential of GIST. Survivin might become a indicator for evaluating the malignant potential of GIST, and it also strengthens the infiltration and metabasis. Survivin might be a potential therapeutic target in GIST.2. VEGF and MVD might also be indicators for evaluating the malignant potential of GIST, while bFGF is not correlated with the malignant potential of GIST. MVD takes part in the infiltration and metabasis of GIST.3. Survivin gene is probably involved in angiogenesis cooperatively with VEGF and bFGF in GIST, and they promote the malignant process of GIST together.4. AI in positive survivin expression group is lower than that in negative survivin expression group. Survivin can promote the progression of GIST by inhibiting cell apoptosis.