title: Hepatitis B virus X protein and hypoxia‑inducible factor-1α stimulate Notch gene expression in liver cancer cells.
abstract: Increasing evidence has demonstrated that Notch genes, including Notch1, Notch2, Notch3 and Notch4, are involved in carcinogenesis. However, the expression and regulation of Notch genes in hepatocellular carcinoma (HCC) tissues have not been fully investigated. In the present study, immunohistochemical and quantitative real-time PCR (qPCR) analyses were performed to examine the expression of Notch genes in normal human liver, HBV-related HCC and paired peritumoral tissues. Additionally, qPCR and western blotting were utilized to investigate the impact of hepatitis B virus X protein (HBx) and hypoxia‑inducible factor-1α (HIF-1α) on the regulation of Notch gene expression. The immunohistochemical and qPCR results showed that the expression levels of Notch1, Notch3 and Notch4 were significantly higher in HCC tissues than the levels in peritumoral and normal liver tissues. However, no significant difference in Notch2 expression was found between HCC and peritumoral tissues. Among the four Notch genes, immunohistochemical analyses found that only the increased level of Notch3 in HCC tissues was positively correlated with vascular invasion of liver cancer (P<0.05). Moreover, we found that overexpression of both HBx and HIF-1α increased the expression of Notch1, Notch3 and Notch4 in HepG2 and Bel-7404 cell lines. In summary, the present study demonstrated that Notch1, Notch3 and Notch4 were upregulated in HCC tissues and that HBx and HIF-1α may be the factors that cause the overexpression of Notch genes. Furthermore, the increased expression of Notch3 was closely related to the vascular invasiveness of HCC.
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Sheng-Li
authors.initials: SL
authors.lastname: Yang
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Quan-Guang
authors.initials: QG
authors.lastname: Ren
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology and Hepatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Pan
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wen
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors.forename: Jian-Li
authors.initials: JL
authors.lastname: Hu
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Hospital of Guiyang Medical College, Guiyang, Guizhou 550001, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of General Surgery, Huanggang Central Hospital, Huanggang, Hubei 438000, P.R. China.
authors.forename: Qian-Jin
authors.initials: QJ
authors.lastname: He
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006515:Hepatitis B virus / Q000472:pathogenicity; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism; D000071656:Receptor, Notch3 / Q000235:genetics / Q000378:metabolism; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497761:NOTCH1 protein, human; C497764:NOTCH2 protein, human; C499374:NOTCH3 protein, human; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein