| Background:Gastric cancer (GC), as a common malignant tumor, has severely threatened people’shealth from worldwide and caused death. The rates of its attack and fatality in China areknown to be higher than the world average level. Despite these high rates, the low rates ofearly diagnosis and survival, poor prognosis, sophisticated causes of the disease,especially the lack of effective early warning, become the main restrains for the diagnosisand treatment of GC. Therefore, the discovery of reliable biomarker for GC early warningand diagnosis remains as a research focus in this field.Both environmental and genetic factors can cause the attack of GC, among which,genetic factor has a closer relations to the disease. Compared to gene mutation, the geneticmarker of the third generation SNP (single nucleotide polymorphism) has been applied inGC related researches for its great advantages. Also, SNP can be used in experiment orclinic diagnosis as a potential genetic marker.PLCE1(phospholipase C epsilon1) is a newly discovered isoenzyme of PL C(phospholipase C) and its structure and function remain unclear. According tobioinformatics analysis, PLCE1protein, containing DNA-binding domain, may beinvolved in RAS-BRAF associated signal pathway which could affect the process of GC.Further analysis shows that PLCE1polymorphisms could influence the post-translationmodification of PLCE1protein such as phosphorylation and methylation. Thepost-translation modification is a key way affecting protein’s bio-function. GWAS(Genome-Wide Association Studies) results show that PLCE1gene polymorphisms areassociated with GC on Chinese Han Population significantly. Han population innorthwestern China are at the high risk of GC. Therefore, the research of GC on thesepeople, and the research on relationship between genetic polymorphism in the PLCE1gene and GC, as well as the research on mechanism will mean a lot to explore therelationship of PLCE1gene and GC.Purposes:The purposes of our research are to explore the correlations of SNPs of PLCE1andassociated risks in GC among Chinese northwestern Han population, to test a newpotential marker for GC diagnosis and early warning, and to find out the expression anddistribution of PLCE1protein in different tumor and pericarcinous tissues. The abovepurposes will help to lay a reliable foundation to researches on PLCE1’s function as well.Methods:We first conducted a contrastive study on human peripheral blood of476GC patientsand481healthy people through Massany analysis on PLCE1gene candidate SNPs ofsample blood and analysis on the relativity of SNPs and GC, so as to screen out the relatedsets.Secondly, we compared GC and corresponding pericarcinous tissues (168cases),GC(168cases) and non-digestive tumor(180cases on lung cancer, mammary cancer andglioma), GC(168cases) and gastric/esophageal squamous cell carcinoma(58cases) on thebases of peripheral blood research. By doing these we discussed the possibility to takePLCE1gene SNPs as genetic marker for GC.To continue our study, we tested mRNA and protein expression of PLCE1gene in GC and the corresponding pericarcinous tissues by immunohistochemical method. After westudied the mechanism of PLCE1protein, its tissue specificity was also discussed bytesting PLCE1protein in16different cancer tissues and pericarcinous tissues.Results:1. Case control study showed that there are three SNPs (rs10509670、 rs3765524、rs2274223) of PLCE1gene relating significantly with GC in northwestern Chines Hanpopulation. Among the three SNPs, rs10509670was newly discovered. Linkagedisequilibrium (LD) and haplotype analysis showed that the two haplotypes wereresponsible for GC risk (hap1: OR=0.78,95%CI,0.61-0.98, P=0.033; hap2: OR=2.51,95%CI,1.51-4.16, P=0.0002).2. Results of tissues sample testing showed that no difference of genetic variationdistribution frequencies existed between GC and paired normal tissues, significantdifference existed between GC and three non-digestive system cancers. These resultshighly suggested that genetic variations of PLCE1in GC tissues were polymorphismsrather than somatic mutations.3. The data showed that both PLCE1A and PLCE1B could be transcripted in GC andtheir adjacent normal tissues in all the groups. The transcription of PLCE1A was higherthan PLCE1B in both protective and risk haplotypes. In protective haplotype, the PLCE1Awas higher in both normal and GC tissues, but in risk haplotype, only the difference in GCtissues was significant. In addition, PLCE1A transcription was significantly higher inprotective haplotype than in risk hyplotype in both normal and GC tissues4. Results showed that PLCE1expression was positive in six normal digestive systemtissues of esophagus, stomach, colon, rectum, liver and pancreas, while varied in relevantcancer tissues. For non-digestive system tissues, PLCE1expression was positive in normaltissues of bladder, cerebrum, kidney, lymph node, mammary and lung cancer tissues. Inaddition, differences still existed in the disparity and expression degree of PLCE1intumors and normal tissues.Conclusion:This study rank the first to research on SNPs and GC risk among Chinese northwestern Han population. Our results provide evidence that PLCE1genepolymorphism is related with the relevant expression level and with GC significantly. Byanalyzing different tumor tissues and pericarcinous tissues, we initially explored theexpression and disparity of PLCE1in other human tissues. Our research not only provedthe effect of PLCE1gene and its polymorphism in GC, but also helped to cure GC andexplore molecular marker for tumor in other tissues. |
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