Hepatitis Bx Antigen Stimulates Expression of a Novel Cellular Gene, URG4, that Promotes Hepatocellular Growth and Survival

Şatıroğlu-Tufan, N. Lale; Lian, Zhaorui; Liu, Jie; Pan, Jingbo; Arbuthnot, Patrick; Kew, Michael C.; Clayton, Marcy; Zhu, Min; Feitelson, Mark A.

doi:10.1038/sj.neo.7900241

Cited by 61 publications

(34 citation statements)

References 37 publications

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“…Previously, we have analyzed the differentially expressed genes in the presence of HBxAg in HepG2 cells, a hepatoblastoma cell line, and showed that HBx upregulates the expression of a novel gene, URG4, which is differentially expressed in tumor compared to non-tumor liver specimens from HBV-infected HCC patients. Over-expression of URG4 in HepG2 and GES-1 cells promoted cell growth and survival in tissue culture and soft agar, and accelerated tumor development in nude mice, suggesting that URG4 may be associated with the onset of tumorigenesis (Satiroglu-Tufan et al, 2002;Song et al, 2006). Over-expression of URG4 in osteosarcoma tissues is well correlated with tumor recurrence and metastasis, as well as with the proliferative activity of osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 88%

“…Previous publications of our group and others have revealed that URG4 over-expression stimulates cell growth in HepG2 and GES-1 cells (Satiroglu-Tufan et al, 2002;Song et al, 2006). Hence, experiments were designed to determine whether the inhibition of URG4 expression could suppress the growth of hepatocarcinoma cells.…”

Section: Rnai-mediated Urg4 Silencing Suppresses the Growth Of Hepg2 mentioning

confidence: 99%

“…URG4 was strongly expressed in hepatitis B-infected liver and in HCC cells, where it costained with HBxAg, and was weakly expressed in uninfected liver, suggesting that URG4 was an effector of HBxAg in vivo. Over-expression of URG4 in HepG2 (Satiroglu-Tufan et al, 2002) and GES-1 cells (Song et al, 2006) promoted cell growth and survival in tissue culture and soft agar, and accelerated tumor development in nude mice, suggesting that URG4 may be associated with the onset of tumorigenesis. Over-expressed URG4 in osteosarcoma tissues is well correlated with tumor recurrence and metastasis, as well as with the proliferative activity of osteosarcoma cells.…”

Section: Introductionmentioning

confidence: 99%

“…HBV encodes a protein known as hepatitis B x antigen (HBxAg or HBx), which appears to participate in the development of HCC (Feitelson et al, 2009). Recently, upregulated gene 4 (URG4, GenBank GeneID: 55665), a novel gene stimulated by HBxAg, was identifi ed by polymerase chain reacby HBxAg, was identifi ed by polymerase chain reac-, was identified by polymerase chain reaction (PCR) select cDNA subtraction, using HBxAg-positive and HBxAg-negative HepG2 cells (Satiroglu-Tufan et al, 2002). URG4 was located on chromosome 7 (7p13).…”

Section: Introductionmentioning

confidence: 99%

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RNA interference-mediated URG4 gene silencing diminishes cyclin D1 mRNA expression in HepG2 cells

Şatıroğlu-Tufan¹,

Dodurga²,

D³

et al. 2010

Genet. Mol. Res.

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ABSTRACT. Up-regulated gene 4 (URG4), stimulated by HBxAg, is a novel gene located on chromosome 7 (7p13). The full-length URG4 clone is 3.607 kb and encodes a polypeptide of 922 amino acids, with a molecular weight of 104 kDa (GeneID: 55665). It promotes cell growth, growth factor-independent survival, and anchorage-independent growth in HepG2 cells, and it accelerates tumor formation in nude mice. Hence, URG4 may be a natural effector of HBxAg and a putative oncogene that contributes to multi-step hepatocarcinogenesis. Cyclin D1 is frequently over-expressed in hepatocellular carcinoma, exhibiting a number of malignant phenotypes. We found that down-regulation of URG4 through RNA interference-mediated silencing suppressed cell proliferation in HepG2 cells. Over-expression of URG4 up-regulated cyclin D1 mRNA expression, whereas RNA interference-mediated URG4 silencing diminished cyclin D1 mRNA expression in HepG2 cells. The data suggest that URG4 may play an important role in the development of hepatocellular carcinoma by partially regulating the expression of cyclin D1 and has potential for use as a therapeutic target for hepatocellular carcinoma.

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Section: Discussionmentioning

confidence: 88%

Section: Rnai-mediated Urg4 Silencing Suppresses the Growth Of Hepg2 mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

RNA interference-mediated URG4 gene silencing diminishes cyclin D1 mRNA expression in HepG2 cells

Şatıroğlu-Tufan¹,

Dodurga²,

D³

et al. 2010

Genet. Mol. Res.

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“…Studies have shown that an abnormal increase in the cellular CCND1 level can cause malignant cell transformation and resistance to apoptosis, thus contributing to the resistance of several tumor cells to chemotherapeutic agents [8,9,10,11]. In addition, studies have indicated that expression of URG4 promotes growth factor-independent survival [12] and URG4 has a role in tumorigenesis by affecting the CCND1 level through bypassing the checkpoint during the G1 to S phase transition [5,12]. Therefore, we suggest that URG4 might act via CCND1 and contribute to uncontrolled proliferation of blasts in the 2 leukemia cases presented here, since overexpression of both CCND1 and URG4 were observed.…”

Section: Discussionmentioning

confidence: 99%

Higher Expression of the Novel Gene Upregulated Gene 4 in Two Acute Lymphoblastic Leukemia Patients with Poor Prednisolone Response

et al. 2012

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Elucidation of the molecular mechanisms of leukemogenesis is important for a better understanding of the prognosis of acute lymphoblastic leukemia (ALL). Studies have shown that the expression of upregulated gene 4 (URG4), which promotes cell growth and survival, is increased in different types of carcinomas including hepatocellular carcinoma, gastric cancer and osteosarcoma. Similarly, higher expression of URG4 and cyclin D1 gene might promote proliferation of the blast cells by causing escape from the G1 checkpoint and entry into the S phase. This study reports the high expression level of URG4 in 2 high-risk ALL patients for the first time in the literature. In conclusion, the higher expression of URG4 in our 2 patients suggests that URG4 might be involved in leukemogenesis. Future studies with a large number of high-risk ALL patients and cell culture studies are needed to demonstrate the exact role of URG4 in leukemogenesis.

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Enhanced cell survival of Hep3B cells by the hepatitis B x antigen effector, URG11, is associated with upregulation of β-catenin

Lian

Liu

et al. 2006

Hepatology

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Intrahepatic expression of hepatitis B x antigen (HBxAg) is associated with the development of hepatocellular carcinoma (HCC), perhaps through trans-activation of selected cellular genes. When this was examined by PowerBlot analysis, upregulated levels of ␤-catenin and several known ␤-catenin effectors were observed in HBxAg-positive compared with HBxAg-negative HepG2 cells. When HBxAg was introduced into Hep3B cells, upregulated expression of wildtype ␤-catenin was observed. This was also observed in Hep3B cells overexpressing the HBxAg upregulated gene, URG11. Upregulated expression of URG11 and ␤-catenin correlated with HBxAg trans-activation function. Transient transfection assays with fragments of the ␤-catenin promoter showed that it was activated by both HBxAg and URG11 and inhibited by URG11-specific small inhibitory RNA. The latter also inhibited the growth of Hep3BX cells in a serumfree medium, which correlated with depressed levels of ␤-catenin. Activation of ␤-catenin effector genes was observed in cells stably expressing HBxAg or overexpressing URG11 compared with control cells transfected with the pTOPFLASH reporter plasmid. Extensive costaining between HBxAg, URG11, and ␤-catenin was observed in infected liver and HCC nodules, suggesting a close relationship in vivo. In conclusion, wild-type ␤-catenin is activated by HBxAg, in part, through the upregulated expression of the HBxAg effector URG11. URG11 stimulates the ␤-catenin promoter and hepatocellular growth and survival. These observations also suggest that URG11 may be a regulatory element in the ␤-catenin signaling pathway and may be a target for chemoprevention of HCC. (HEPATOLOGY 2006;43:415-424.)

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Hepatitis Bx Antigen Stimulates Expression of a Novel Cellular Gene, URG4, that Promotes Hepatocellular Growth and Survival

Cited by 61 publications

References 37 publications

RNA interference-mediated URG4 gene silencing diminishes cyclin D1 mRNA expression in HepG2 cells

RNA interference-mediated URG4 gene silencing diminishes cyclin D1 mRNA expression in HepG2 cells

Higher Expression of the Novel Gene Upregulated Gene 4 in Two Acute Lymphoblastic Leukemia Patients with Poor Prednisolone Response

Enhanced cell survival of Hep3B cells by the hepatitis B x antigen effector, URG11, is associated with upregulation of β-catenin

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