Altered growth and spontaneous transformation of cells cultured from v-jun transgenic mice recapitulate wound-induced multistage tumorigenesis.
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Abstract:
H-2K/v-jun transgenic mice develop sarcomas at sites of wounding via a multistep process characterized by discrete pathological stages. To study this progression in vitro, cells from different stages of tumorigenesis were cultured and examined for their growth properties. The results show that whereas transgenic fibroblasts do not manifest enhanced proliferative potential in vivo in the absence of wounding, they do show obvious proliferative advantage relative to nontransgenic fibroblasts in vitro, including the capacity for indefinite growth. In addition, relative to nontransgenic fibroblasts, transgenic cells show altered sensitivity to platelet-derived growth factor and tumor necrosis factor alpha, both of which are known to be mobilized during wounding. No obvious differences in growth potential are observed between transgenic fibroblasts and cells cultured from wound-induced premalignant lesions, and confluent cultures of both cell populations give rise to spontaneous foci of transformed myogenic and nonmyogenic cells that resemble those of late-stage malignant wound sarcomas. Relative to transgenic fibroblast cultures, however, premalignant lesion cultures segregate transformed cells at a greater frequency and after shorter intervals of in vitro growth. The results suggest that wound-induced multistage tumorigenesis can be recapitulated in vitro and that cells cultured from different stages of tumorigenesis retain biological properties that reflect the pathological stage from which they are derived.Cite
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STK33 has been reported to play an important role in cancer cell proliferation. We investigated the role of STK33 in hepatocellular carcinoma (HCC) and its underlying mechanisms.Design
251 patients with HCC were analysed for association between STK33 expression and clinical stage and survival rate. Tamoxifen (TAM)-inducible, hepatocyte-specific STK33 transgenic and knockout mice models were used to study the role of STK33 in liver tumorigenesis. HCC cell lines were used to study the role of STK33 in cell proliferation in vitro and in vivo.Results
STK33 expression was found to be frequently upregulated in patients with HCC. Significant associations were found between increased expression of STK33 and advanced HCC staging and shorter disease-free survival of patients. Overexpression of STK33 increased HCC cell proliferation both in vitro and in vivo, whereas suppression of STK33 inhibited this effect. Using a TAM-inducible, hepatocyte-specific STK33 transgenic mouse model, we found that overexpression of STK33 resulted in increased hepatocyte proliferation, leading to tumour cell burst. Using a TAM-inducible, hepatocyte-specific STK33 knockout mouse model, we found that, when subjected to the diethylnitrosamine (DEN) liver cancer bioassay, STK33KOflox/flox, Alb-ERT2-Cre mice exhibited a markedly lower incidence of tumour formation compared with control mice. The underlying mechanism may be that STK33 binds directly to c-Myc and increases its transcriptional activity. In particular, the C-terminus of STK33 blocks STK33/c-Myc association, downregulates HCC cell proliferation, and reduces DEN-induced liver tumour cell number and tumour size.Conclusions
STK33 plays an essential role in hepatocellular proliferation and liver tumorigenesis. The C-terminus of STK33 could be a potential therapeutic target in the treatment of patients with STK33-overexpressed HCC.Liver Cancer
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Activating mutations in the PI3K/AKT pathway are present in majority of breast cancer. The gain of function mutation E17K of AKT1, was found in 8% of breast cancers, especially ductal carcinomas, but several studies performed so far have failed to define the real role of this mutation in the breast tissue trnsformation. To investigate the role of the AKT1E17K in breast tumorigenesis, we explored the phenotype of a new mouse model which express the mutant transgene in mammary epithelium. The expression of AKT1E17K enhances the activity of the kinase and the phosphorilation status of downstream substrates, such as FOXO1 and GSK3α/β. In addition, transgenic mice showed an increased cellularity 8-10 times higher than control mice breast tissues. Moreover 70% of transgenic mice expressing the mutant form of AKT1 develop ductal carcinomas from medium to high grade. We have identified also the contribution of AKT1E17K in the generation and maintenance of putative breast cancer stem cells. Finally, using a pharmacological study, we were able to slow down tumor formation by inhibiting downstream effect of AKT1 pathway. All together these data have allowed us to demonstrate that AKT1E17K is itself capable to induct the onset of ductal carcinoma in transgenic mice.
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14-3-3ζ is overexpressed in more than 40% of breast cancers, but its pathophysiologic relevance to tumorigenesis has not been established. Here, we show that 14-3-3ζ overexpression is sufficient to induce tumorigenesis in a transgenic mouse model of breast cancer. MMTV-LTR promoter-driven HA-14-3-3ζ transgenic mice (MMTV-HA-14-3-3ζ) developed mammary tumors, whereas control mice did not. Whey acidic protein promoter-driven HA-14-3-3ζ transgenic mice (WAP-HA-14-3-3ζ) developed hyperplastic lesions and showed increased susceptibility to carcinogen-induced tumorigenesis. When crossed with MMTV-neu transgenic mice, 14-3-3ζ.neu transgenic mice exhibited accelerated mammary tumorigenesis and metastasis compared with MMTV-neu mice. Mechanistically, 14-3-3ζ overexpression enhanced MAPK/c-Jun signaling, leading to increased miR-221 transcription, which inhibited p27 CDKI translation and, consequently, promoted cell proliferation. Importantly, this 14-3-3ζ-miR-221-p27 proliferation axis is also functioning in breast tumors in patients and is associated with high-grade cancers. Taken together, our findings show that overexpression of 14-3-3ζ has a causal role in mammary tumorigenesis and progression, acting through miR-221 in cooperation with known oncogenic events to drive neoplastic cell proliferation.
Mammary tumor
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Here, we investigated changes in apoptosis during tumor progression by analyzing the effect of coexpressing various antiapoptotic genes on the multistage process of c-myc-induced hepatocarcinogenesis in transgenic mice. Whereas continuous c-myc gene overexpression in the liver led to cellular hepatocarcinoma, the coexpression of the bcl-2 gene inhibited the emergence of liver tumors, by inhibiting a pretumoral phase characterized by increased proliferation and apoptosis. This antioncogenic effect was specific to Bcl-2 and was not shared by other antiapoptotic genes such as bcl-xL and a dominant negative form of p53. Thus, we have shown that Bcl-2 can have a tumor suppressor effect in vivo on c-myc-induced hepatocarcinogenesis during the emergence of neoplastic foci.
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Malignant Transformation
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Abstract MYC is frequently overexpressed in human cancers, but the downstream events contributing to tumorigenesis remain incompletely understood. MYC encodes an oncogenic transcription factor, of which target genes presumably contribute to cellular transformation. Although Myc regulates about 15% of genes and combinations of target genes are likely required for tumorigenesis, we studied in depth the expression of the Myc target gene, JPO1/CDCA7, in human cancers and its ability to provoke tumorigenesis in transgenic mice. JPO1/CDCA7 is frequently overexpressed in human cancers, and in particular, its expression is highly elevated in chronic myelogenous leukemia blast crisis as compared with the chronic phase. In murine lymphoid tissues, ectopic human JPO1/CDCA7 expression resulted in a 2-fold increased risk of lymphoid malignancies at 1 year. The transgene, which was driven by the H2-K promoter, exhibited leaky expression in nonlymphoid tissues such as kidney. We observed a significant increased incidence of transgenic animal solid tumors, which were not seen in littermate controls. These observations suggest that JPO1/CDCA7 may contribute to Myc-mediated tumorigenesis.
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E2F1
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p53 family proteins carry on a wide spectrum of biological functions from differentiation, cell cycle arrest, apoptosis and chemosensitivity of tumors. Conversely, N-terminally truncated p73 (DNp73) functions as a potent inhibitor of all these tumor suppressor properties, implicating its participation in malignant transformation and oncogenesis. Several reports indicated considerable up-regulation of DNp73 in hepatocellular carcinoma (HCC) that correlates with reduced survival of patients, but little is known about the functional significance of DNp73 to tumorigenesis in vivo due to the lack of an appropriate model. To address this, we generated transgenic mice in which DNp73 expression is directed to the liver by the albumin promoter. Gene expression was tested by mRNA and protein analyses. Transgenic mice exhibited prominent hepatic histological abnormalities including increased hepatocyte proliferation resulting in preneoplastic lesions (liver cell adenomas) at 3–4 months. Among 12- to 20-month-old mice, 83% of animals developed hepatic carcinoma. HCC displayed a significant increase of hyperphosphorylated inactive retinoblastoma, whereas p53-regulated inhibitors of cell cycle progression were down-regulated in the tumors. Our data firmly establish the unique oncogenic capability of DNp73 to drive hepatocarcinogenesis in vivo , supporting its significance as a marker for disease severity in patients and as target for cancer prevention. This model offers new opportunities to further delineate DNp73-mediated liver oncogenesis but may also enable the development of more effective cancer therapies.
Retinoblastoma
Liver Cancer
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