title: The rs391957 variant cis-regulating oncogene GRP78 expression contributes to the risk of hepatocellular carcinoma.
abstract: Glucose-regulated protein 78 (GRP78) is one of the most important responders to disease-related stress. We assessed the association of the promoter polymorphisms of GRP78 with risk of hepatocellular carcinoma (HCC) and GRP78 expression in a Chinese population. We examined 1007 patients undergoing diagnostic HCC and 810 unrelated healthy controls. Mechanisms by which the GRP78 promoter polymorphism modulates HCC risk and GRP78 levels were analyzed. The promoter haplotype and diplotype carrying rs391957 (-415bp) allele G and genotype GG was strongly associated with HCC risk. Luciferase reporter assays indicated that the promoter carrying rs391957 allele G (haplotype GCCd) showed increased activity in HepG2 cells and Hela cells. rs391957 was also shown to increase the affinity of the transcriptional activator Ets-2, the resistance to apoptosis, as well as cell instability in stressful microenvironment. Furthermore, compared with allele A, rs391957 allele G was associated with higher levels of GRP78 mRNA and protein in HCC tissues. These findings provided new insights into the pathogenesis of HCC and an unexpected effect of the interaction between rs391957 and Ets-2 on hepatocarcinogenesis, and especially supported the hypothesis that stress-related and evolutionarily conserved genetic variant(s) influencing transcriptional regulation could predict susceptibilities.
authors: Guangdong Province Key Laboratory of Medical Molecular Diagnosis, Guangdong Medical College, Dongguan, China.
authors: Xiao
authors: X
authors: Zhu
authors: Jinfang
authors: J
authors: Zhang
authors: Wenguo
authors: W
authors: Fan
authors: Fang
authors: F
authors: Wang
authors: Hong
authors: H
authors: Yao
authors: Zifeng
authors: Z
authors: Wang
authors: Shengping
authors: S
authors: Hou
authors: Yinghong
authors: Y
authors: Tian
authors: Weiming
authors: W
authors: Fu
authors: Dan
authors: D
authors: Xie
authors: Wei
authors: W
authors: Zhu
authors: Jun
authors: J
authors: Long
authors: Leijie
authors: L
authors: Wu
authors: Xuebao
authors: X
authors: Zheng
authors: Hsiangfu
authors: H
authors: Kung
authors: Keyuan
authors: K
authors: Zhou
authors: Marie C M
authors: MC
authors: Lin
authors: Hui
authors: H
authors: Luo
authors: Dongpei
authors: D
authors: Li
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D050787:Proto-Oncogene Protein c-ets-2 / Q000235:genetics / Q000378:metabolism*; D012306:Risk; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; C494069:ETS2 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D050787:Proto-Oncogene Protein c-ets-2