| ObjectivesHuman apurinic/apyrimidinic endonuclease1(APE1) is the key protein of base excisionrepair (BER) pathway, responsible for the excision of AP site. The former experimentsshowed that the expression level and subcellular localization of APE1was related to thesensitivity of chemotherapy and radiothepray in tumor cells. And the polymorphism of APE1(Asp148Glu) was reported to have association with cancer susceptibility among differentpopulation. In this research, the association of APE1with tumorigenesis and cancerdevelopment was studied to comfirm the characteristics and risk people among Chinesepopulation, and to provide the exprerimental evidences for the mechanisms of anticancer drugsensitivity and susceptibility.MethodsThe whole research contaiend two part. In the first part, the733non-small cell lungcancer tissue samples were analyzed by IHC. The expression of six chemotheraputic relatedproteins, such as APE1, BRCA1, ERCC1, TUBB3, TS and RRM1, were evaluated anddevided as negative expression and positive expression according to the expression level. Theexpression characteristics of the six proteins were observed and the relationships between theproteins and histological types as well as each other proteins were analyzed. In the secondpart,247colorectal cases and300cancer-free controls were enrolled. The peripheral bloodsamples were obtained for each subject and the genome DNAs were obtained. The fourpolymorphisms among BER pathway (OGG1Ser326Cys, APE1Asp148Glu,-141T/G in thepromoter region and XRCC1Arg399Gln)was analyzed by PCR-CTPP. The logistic regressionmodel was conducted to evaluate the relationships between these polymorphisms and thecolorectal cancer susceptibility. ResultsIn NSCLC, the expression of BRCA1, TUBB3and TS was different in differenthistological types (P<0.01), and the expression level of these3proteins were related to thehistological types(P<0.01). The positive rate of BRCA1and TS were lowest inadenocarcinomas (16.77%and6.13%), while the TUBB3was lowest in squamous cellcancer(27.39%). There were widely relationships between these6proteins. APE1waspositively related with ERCC1, RRM1and TUBB3(r=0.316, r=0.222and r=0.107，P<0.01),and slightly related with BRCA1(r=0.083, P<0.05). ERCC1was positively associated withBRCA1, RRM1and TS (r=0.214, r=0.109and r=0.129, P<0.05); BRCA1was positivelyrelated with TS and RRM1(r=0.188and0.094, respectively); The TUBB3was also slightlyassociated with RRM1(r=0.090). In colorectal cancer, the APE1148Glu/Glu genotype wassignificantly higher in cases than controls (28.34%vs.13.67%, P<0.001). Compared with theAsp/Asp genotype, individuals with Glu/Glu genotype showed an increased risk of colorectalcancer (OR=2.411, P<0.001). The frequency of APE1Glu allele was significantly higher inCRC patients than controls (46.56%vs.36.50%; OR=1.516, P<0.001). The subgroup analysisrevealed the APE1148Glu/Glu genotype was associated with increased risk of colorectalcancer among smokers or non-smokers (Smokers: OR=3.299, Non-smokers: OR=2.336;P<0.05). Compared with the homozygous genotypes (Arg/Arg combined Gln/Gln) of XRCC1,the Arg/Gln showed a protective effect among smokers (OR=0.289, P<0.001), and theinteraction between smoking status and the relationship of XRCC1with CRC was observed(Interaction P<0.05). The APE1-141T/G genotype in the promoter region was related withthe decreaed risk of CRC among subjects with a BMI index less than25kg/m2(OR=0.214,P<0.05). The interaction test was positive between BMI index and APE1-141T/Gpolymorphism (Interaction P<0.05).ConclusionsThe expression of chemotheraputic related proteins was related with NSCLCpathological types. And the expression levels of these proteins were widely associated witheach other. The combined detection of these proteins may play an important role inoptimization of chemotherapy and conduction of individual therapy design. The APE1Asp148Glu polymorphism was associated with increased CRC risk. The smoking status mayalter the association between XRCC1Arg399Gln polymorphism and CRC risk among Chinese Han population. |
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