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Purpose: THBS1 is a large matrix glycoprotein of multiple functions, and well known for its potent anti-angiogenesis activity.It is believed to be involved in regulation of cell adhesion, proliferation and mobility.In vitro and in vivo animal studies have clearly shown that THB1 plays an important role in cancer development.Clinicopathological studies also have suggested that the altered expression level is involved in human carcinogenesis.However, the direct genetic evidence for its role in cancer is still lacking.This study is to further reveal functional differences in carcinogenesis caused by polymorphic THBS1 proteins from the genetic point of view.Experimental Design: A case-control study was conducted in a randomly recruited population of 283 patients and 283 healthy people in Fuzhou city, in Southeast China.The case group included 102 high-differentiated carcinoma (HD, composed of 2 well-and 100 moderate-differentiated), 181 low-differentiated carcinoma (LD, composed of 22 moderate-poorly, 127 of poorly-differentiated adenocarcinoma and 32 diffuse type carcinoma).Individuals were genotyped for a non-synonymous single nucleotide polymorphism (SNP), A523T in THBS1.Genotypic distributions between patient and control groups were compared for correlations with cancer susceptibility.Associations with nodal metastasis and several other clinicopathological features were also analyzed using univariate tests, multivariate logistic regression modeling analyses.Results: After adjustment using logistic regression for the potential confounding effects of gender, age, homozygous THBS1 523AA was associated with the occurrence of HD with adjusted odd ratios (ORadjusted) of 2.6, 95% confidential interval (95% CI) of 1.3-5.1,p of 0.02.No association of homozygous 523AA with LD is observed.The association of homozygous 523AA with the higher status in differentiation is also statistically evident (Padjusted=0.03, ORadjusted 2.2, 95% CI of 1.1-4.5).The lack of association of homozygous 523AA with the occurrence of LD and no under-presentation of homozygous 523AA in LD in comparison to HD (ORadjusted=1.1 vs.2.6), indicates that THBS1 523AA increases the susceptibility to HD not by converting more LD to HD.Interestingly, significant associations were observed between homozygous 523TT (the other allele) with increased risk of nodal metastasis in HD with ORadjusted of 2.5, 95% CI of.(p=0.03).Conclusion: The present study has demonstrated significant associations between the increased risks of occurrence with THBS1 523AA and nodal metastasis with THBS1 523TT in HD.This data also indicate a potential role of THBS1 in regulation of differentiation during carcinogenesis and metastasis during tumor progression.At the level of human genetics, our data have confirmed the importance of THBS1 in the gastric carcinogenesis,added to the information needed for risk and prognostic evaluation, and also provided insights into the biochemical properties of THBS1.In light of THBS1 being a potential therapeutic agent, further investigation of the underlying molecular mechanisms for both roles is critical for its application.