Association Between Hedgehog Signaling Pathway Gene Promoter Genetic Variation And The Susceptibility To Hepatocellular Carcinoma

ObjectivesIt is known that the progression of Primary Hepatic Carcinoma (HCC) occurs is an activation of interaction between multiple genetic and environmental factors. Hedgehog (Hh) signaling pathway plays a critical role in the embryonic development of mammals by controlling cell proliferation and differentiation. It is also becoming increasingly clear that this pathway have a crucial role in the liver cells from the endoderm, hepatic progenitor cells, embryonic stem cells into liver cells of each stage. During liver cell malignant development and transformation process of cancer, It has been found that the hedgehog signaling pathway plays an important role in the abnormal activation of embryo, which is closely related to the occurrence and development of HCC. The pathway of gene single nucleotide polymorphism in the promoter region (SNPs) may lead to the abnormal gene function by affecting the individual genetic susceptibility to hepatocellular carcinoma. This article applied to combined hospital-based case-control studies with laboratory detection,1041 HCC patients for case and 1074 cases of non tumor individual control as the research object, we assess the association between the. pathway of gene single nucleotide polymorphism (SNPs), alone and interaction with environmental factors with the risk of hepatocellular carcinoma (HCC), identify the liver cancer susceptibility genes and genetic mutation, to elucidate its biological function, and to reveal the molecular mechanism of HCC. This study will help to understand molecular genetic mechanisms for HCC, our study will provide new ideas and theoretical basis for the prevention of hepatocellular carcinoma.MethodsOur study was used the case-control study.1041 HCC patients were included for case in this study during June 2007 to April 2011, who were recruited from Affiliated Tumor Hospital of Guangxi Medical University and the first Affiliated Hospital of Guangxi Medical University. All cases HCC patients were newly diagnosed with clinical symptom, serum tumor biomarker and histology, which should not only had noprevious medical history of malignant tumor of other organ and liver metastasis, but also did not receive radiation therapy and/or anticancer drugs.There were1074 cance-free controls that who were recruited from the first Affiliated Hospital of Guangxi Medical University in the same period,all controls were matched frequency with the cases by sex, race, age in this study. We using questionnaire to collect the general demographic information and related environmental exposure factors from all the objects. Genomic DNA was isolated from3ml venous blood sample using the Phenol-Chloroform method, which were donated by each subject. All these fourteen selected SNPs were genotyped by the sequenom mass array.the difference of the continuous variable and the categorieal variable were respectively tested by the t test and χ2 test, Odds ratios (ORs) and 95%confidence intervals (CIs) were analysed by Multivariate logistic regression models in this study. And we explored the association between the above fourteen potentially functional SNPs and its interaction with environmental factors to find the genetic susceptibility of HCC. All above statistical analyses were performed with SAS software (version 9.1.3).Multivariate Logistic regression analysis method was also used to find the association between the genotype of above fourteen SNPs and the experimental exposure and the genetic susceptibility to hepatocellular carcinoma. We analyze all the data from the experimental results with software (version 9.1.3); Multivariate Logistic regression analysis and other statistical methods were used to evaluation of SNPs, gene environment factors (such as HBV infection, alcohol, smoking) role in the pathogenesis of HCC.Results(1) The general characteristics of the subjectsThere was statistical differences in the distributions of age between cases and controls (P<0.05),but there was no statistical differences were found between cases and controls in the distributions of sex (P>0.05). But, there was more likely that the cases were to be smokers, drinkers, and HBV infection indivuals than the controls (P< 0.001).(2)Associations between the hedgehog signaling pathway SNPs and risk of HCCWe performed Multivariate Logistic regression analysis after adjusted by age, sex, smoking, drinking status and HBV infection, The mutant allele G carriers of liver cancer is 0.67 times as The wild type allele A in the AG genotype of rs34237608 (A>G) in the STK36 gene (AG/GG vs AA:OR=0.67,95%CI: 0.48-0.95, P=0.025),which can reduce the risk of hepatocellular carcinoma; However, there were no statistical significance with hepatocellular carcinoma (P>0.05) in the PTCH gene rs16909919 (C>T), GLI1 gene rs2242578 (G>C)、 rs10783827 (G>T)、rs1344645 (G>T), GLI3 gene rs10951668 (A>C), STK36 gene rs2241527(G>A), HHIP gene rs7689420 (C>T). rs7675744 (T>C)、 rs72617420(A>C)、rs6845999 (C>T)、rs1355603 (C>T)、There were also no found statistical significance association with hepatocellular carcinoma in both dominance model and recessive model (P>0.05) in Guangxi Zhuang Autonomous Region.(3) Stratification analysis of HCC risk and rs34237608No significant gene-environment interactions on the risk of HCC between between the rs34237608 and environmental factors such as age, sex, drinking, smoking statusand HBV infection (P> 0.05).ConclusionThe results of our analyses, there has statistical significance between the risk of hepatocellular carcinoma in Guangxi and the mutant allele G in the genotype of rs34237608 (A>G) in the STK36 gene, it indicate that that the mutant allele G in the genotype of rs34237608 could reduce the risk of hepatocellular carcinoma, but further functional studies and further validation are been needed in different population.