Association Of Thrombospondins And Its Snp With Occurrence And Development Of Gastric Carcinoma

Gastric carcinoma is one of the most devastating human cancer and it's the second largest type of malignancy in terms of death incidences in China . The Thrombospondins (THBS) belong to a family of extracellular maxtric glycoprotein having multifunctions ,which serve to regulate the occurrence and development of cancer. This study investigates the role of THBS and its single nucleotide polymorphism on the occurrence and development of gastric carcinoma, which provides theoretical bases and experimental data for clinical diagnosis, treatment and prognosis of gastric carcinoma.I. Clinical Significance of Thrombospondin-1 Expression in Gastric CarcinomaIn this study, we quantitatively measured the expression level of THBS-1 mRNA in 82 primary gastric carcinoma tissues and their normal tissues using Real-time PCR. We studied the expression of THBS-1, a-SMA,CD34 in gastric carcinoma tissues through immunohistochemical Staining. Furthermore the correlation of THBS-1 mRNA expression level with clinicopathological features was evaluated . The results were as follows:1. THBS-1 mRNA expression in the tissue of gastric carcinoma was significantly higher than that in adjacent non-cancerous stomach tissues . Tumor THBS-1 mRNA expression level was significantly related to lymph node metastasis, tumor size and age.2. THBS-1 protein was mainly located in myofibroblasts of the stroma, but undetectable in tumor cell.3. The activation of myofibroblasts in gastric carcinoma was significantly related to lymph node metastasis and tumor size.Conclusion: The results of this study show for the first time that in the process of development of gastric cancer , THBS-1 might be used as activator of TGF-? to stimulate fibroblasts into myofibroblasts in the cancer environment to trigger tumor growth and lymph node metastasis .II. Clinical Significance of other Thrombospondins Expression in Gastric CarcinomaIn this study, we quantitatively measured the expression level of THBS-2,-3,-4 mRNA in 82 primary gastric carcinoma tissues and their normal tissues using Real-time PCR. We investigated the expression of MMP-9,CD34 in gastric carcinoma tissues through immunohistochemical staining. Furthermore the correlation of THBS-1 mRNA expression level with clinicopathological features , microvessel density (MVD) and MMP-9 was evaluated . The results were as follows.1. THBS-2,-4 mRNA expression in the tissue of gastric carcinoma was significantly higher than that in adjacent non-cancerous stomach tissues .2. Tumor THBS-4 mRNA expression level was significantly related to tumor size ,lymph node metastasis and tissue differentiation.3. Correlation between THBS-4 mRNA expression in the tissue of gastric carcinoma and MVD was positive(R=0.67,P <0.01).4. Tumor THBS-4 mRNA expression level was significantly related to expression of MMP-9(P =0.008).Conclusion: THBS-2 may be related to the occurrence of gastric cancer. THBS-4 may play an important role in the occurrence and progression of gastric carcinoma and the high expression of THBS-4 may regulate tumor growth and metastasis through effect of angiogenesis and MMP-9 expression in gastric carcinoma.THBS-4 might be a new index of poor prognostic in gastric carcinoma.III. Association between single nucleotide polymorphism of THBS-1,-2 and the occurrence and progression of gastric carcinomaOur research explored the relationship of THBS family genetic polymorphism such as rs2292305,rs2236741,rs2228261,rs3743125,rs8089,rs1132742 and susceptibility to primary gastric carcinoma in 283 cases gastric carcinoma and 283 cases normal human by case and control study by PCR-RFLP and MALDI-TOF-MS .Combining clinical data ,the major aims of our research were the relationship between genetic polymorphisms and suseeptibility to gastric carcinoma. The results were as follows:1. In intestinal gastric carcinoma group ,CC genotype of rs2292305 had a significantly higher risk with 2.1 fold(OR=2.1,95 % CI:1.12-3.82; P=0.025)when compared with CT or TT genotype,which indicated that CC genotype of rs2292305 had a significant relationship with the occuence. However, TT genotype had a comparatively lower risk in metastasis and invasion when compared with CT or CC, which showed that TT genotype might reduce the risk for metastasis and invasion of gastric carcinoma.2. In intestinal gastric carcinoma group ,CC genotype of rs3743125 and rs2228261 had a significantly lower risk(OR=0.37,95 (%) CI0.18-1.26; P=0.02. OR=0.37,95 (%) CI:0.21-1.56; P=0.042) in metastasis when compared with CT or TT,which showed that TT genotype might lower the risk for the metastasis of gastric carcinoma.3. The variant THBS-2 genotype(rs3743125) was highly associated with tissue differentiation of gastric carcinoma.4. In diffuse gastric carcinoma group ,TT genotype of THBS-2(rs8089) had a significantly higher risk in invasion with 2.6 fold(OR=2.6,95 (%) CI: 1.37-3.9; P=0.043 P=0.025)when compared with CT or TT genotype,which showed that TT genotype of rs8089 might increase.the risk for the invasion of gastric carcinoma.5. There are four main THBS-1 haplotypes such as CCTC,TTCT,CTCT,CCCC reconstructed by PHASE software. CCCC haplotype was found to relate significantly to the susceptibility to gastric carcinoma .Conclusion: THBS family genetic polymorphism such as rs2292305,rs3743125,rs2228261,and rs8089 was significantly related with the occurrence and progression of gastric carcinoma. Moreover, CC-C haplotype of THBS-1 reconstructed by PHASE software was found to be related significantly with the susceptibility to gastric carcinoma ,which might be a mole index of susceptibility in gastric carcinoma. In summary, expression of THBS family and its SNP were highly related to the occurrence and development of gastric carcinoma.