Transgenic animals as models for hepatocarcinogenesis

Santoni-Rugiu, Eric; Thorgeirsson, Snorri S.

doi:10.1007/978-94-011-4932-7_4

Cited by 16 publications

(24 citation statements)

References 180 publications

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“…In support of this hypothesis, overexpression of cyclin A2 or E2F1 has been shown to directly facilitate transformation of cultured cells and to cause tumorigenesis in animals (Desdouets et al, 1995;Amati et al, 1998). Overexpression of each of these proteins has been reported in the pre-malignant liver tissue and spontaneous liver tumors in c-myc transgenic mice (Santoni-Rugiu et al, 1998). Transfection of ®broblasts with c-myc has also been shown to induce e2f1, which is independent of pRB phosphorylation (Leone et al, 1997), indicating that this e ect may result directly from increased E2F1 protein, a short-cut mechanism that bypasses the cyclin-cdk-pRB pathway.…”

Section: Discussionmentioning

confidence: 88%

“…In contrast, the relationship between c-Myc and cyclin D1 is still under debate in the literature (Facchini et al, 1998;Dang, 1999). The 5'-¯anking region of the cyclin D1 gene in mouse and human contains a c-Myc recognition site (Daksis et al, 1994), and expression of cyclin D1 has been shown to be induced in some c-myc-expressing tumor cells (Facchini et al, 1998;Dang, 1999), in liver tissue, and in liver tumors from mice carrying a c-myc transgene under the control of the albumin gene promoter (Santoni-Rugiu et al, 1998). These data seem to suggest that cyclin D1 may be a direct target of activation by c-Myc.…”

Section: Introductionmentioning

confidence: 99%

“…This implies that E2F1 plays a central role in cancer development (Johnson et al, 1998). Overexpression of E2F1 is an intriguing mechanism for its activation in the context of c-Mycinduced carcinogenesis, since E2F1 expression has been shown to be induced in liver from c-myc transgenic mice (Santoni-Rugiu et al, 1998) and in ®broblasts transfected with the c-myc gene (Leone et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Cell cycle basis for the onset and progression of c-Myc-induced, TGFα-enhanced mouse mammary gland carcinogenesis

et al. 2000

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Using single and double transgenic mouse models, we investigated how c-Myc modulates the mammary epithelial cell cycle to induce cancer and how TGFa enhanced the process. In c-myc transgenic mice, c-myc expression was high in the hyperplastic mammary epithelium and in the majority of tumor areas. However, the tumors displayed focal areas of low expression of cmyc but high rates of proliferation. In contrast to E2F1 and cyclin A2, which were induced and co-localized with c-myc expression, induction of cyclins D1 and E occurred only in these tumor foci. Overexpression of cyclin D1 also occurred in the hyperplastic epithelium of tgfa-single and tgfa/c-myc-double transgenic mice. In tgfa/c-myc tumors, cells positive for cyclins D1 and E were randomly spread, without showing a reciprocal relationship to c-myc expression. In contrast to c-myc tumors, most tgfa/c-myc tumors showed undetectable levels of retinoblastoma protein (pRB), and the loss of pRB occurred in some cases at the mRNA level. These results suggest that E2F1 and cyclin A2 may be induced by c-Myc to mediate the onset of mammary cancer, whereas overexpression of cyclins D1 and E may occur later to facilitate tumor progression. TGFa may play its synergistic role, at least in part, by inducing cyclin D1 and facilitating the loss of pRB.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cell cycle basis for the onset and progression of c-Myc-induced, TGFα-enhanced mouse mammary gland carcinogenesis

et al. 2000

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“…Nevertheless, recent data have shown that deregulation of E2F plays a key role in the upregulation of PIN1 in breast cancer . Since deregulation of the retinoblastoma pathway has also been reported in HCC (Santoni-Rugiu et al, 1998), deregulation of the Rb/E2F pathway may be responsible for PIN1 overexpression in HCC.…”

Section: Introduction Results and Discussionmentioning

confidence: 99%

PIN1 overexpression and β-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma

et al. 2004

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The peptidyl-proplyl-isomerase, PIN1, upregulates b-catenin by inhibiting its interaction with APC. b-catenin accumulation occurs in about 70% of hepatocellular carcinoma (HCC), of which only 20% are due to b-catenin mutations. The role of PIN1 in b-catenin upregulation in HCC was investigated. PIN1 was shown to be overexpressed in more than 50% of HCC. All cases with PIN1 overexpression also showed b-catenin accumulation, with 68% of cases showing concomitant b-catenin and cyclin D1 accumulation. PIN1 was shown to contribute to b-catenin and cyclin D1 overexpression directly by in vitro cell-line transfection experiments. Finally, we showed that PIN1 overexpression and b-catenin gene mutations appeared to be mutually exclusive events, leading to b-catenin accumulation in HCC. These results showed that PIN1 overexpression leading to b-catenin accumulation might be a critical event in hepatocarcinogenesis, and that PIN1 is a potential target for therapeutic intervention in HCC.

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“…These changes could occur in a variety of cellular genes leading to escape from normal cellular and environmental controls. So far, over 20 cellular genes down-or up-regulated or mutated in HCC such as ras (Ogata et al, 1991;Kim et al, 2001), c-myc, c-fos, and c-jun (Kawate et al, 1999;Yuen, et al, 2001), rho (Genda et al, 1999), TGFa (Chung et al, 2000), HGF and c-met (Ueki et al, 1997), c-erbB-2 (Collier et al, 1992), IGF-II (Takeda et al, 1996), u-PA (de Petro et al, 1998), MXR7 (Hsu et al, 1997), MDM2 (Endo et al, 2000), MAGE (Tahara et al, 1999), matrix metalloproteinase (Musso et al, 1997), Smads (Yakicier et al, 1999), p53 (Shimizu et al, 1999;Rashid et al, 1999), pRB Santoni-Rugiu et al, 1998), p16INK4 Liew et al, 1999), p21 WAF1/CIP1 , p27 Kip1 (Chen et al, 2000;Tannapfel et al, 2000), PTEN (Fujiwara et al, 2000;Yao et al, 1999), E-cadherin ), beta-catenin (de La Coste et al, 1998 and AXIN1 (Satoh et al, 2000) have been described in humans and mice. Many of them are involved in deregulation of intracellular signal transduction and cell cycle, leading eventually to an uncontrolled proliferation of cancerous cells.…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning and characterization of a novel gene which is highly expressed in hepatocellular carcinoma

et al. 2002

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To gain new insight into the molecular mechanism underlying the pathogenesis of human primary hepatocellular carcinoma (HCC), we searched for HCC-specific molecules through screening genes that are differentially expressed between cancerous and noncancerous counterparts of liver and identified a novel HCC-associated gene, HCCA1 encoding a *80 kDa cytoplasmic protein that contains several proline-rich motifs likely for SH3-binding. HCCA1 transcript, albeit present in some adult tissues, is up-regulated selectively in HCC but not in other tumor cells. High expression of HCCA1 occurs as a late event frequently (89.2%) in HCCs and correlated significantly with the degree of tumor progression. When treated with antisense oligonucleotides to HCCA1, HCCA1 expression in HCC cells (HuH-7) was effectively suppressed and cell growth was down-regulated in a time-and dose-dependent manner. Furthermore, HuH-7 cells harboring the HCCA1 antisense expression clone displayed a remarkably reduced efficiency in colony formation. Together, these data strongly suggest that HCCA1 is a positive effector in cell proliferation and contributes to HCC carcinogenesis and progression. We believe that this protein will serve as a novel useful marker for HCC and is a potential target for pharmaceutical intervention of this malignant disease.

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Transgenic animals as models for hepatocarcinogenesis

Cited by 16 publications

References 180 publications

Cell cycle basis for the onset and progression of c-Myc-induced, TGFα-enhanced mouse mammary gland carcinogenesis

Cell cycle basis for the onset and progression of c-Myc-induced, TGFα-enhanced mouse mammary gland carcinogenesis

PIN1 overexpression and β-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma

Molecular cloning and characterization of a novel gene which is highly expressed in hepatocellular carcinoma

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