ACGH analysis of liver tumors generated in C57BL/6J mice with a liver specific loss of Trp53-/- [Agilent-027411]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE156252 | GEO | 2021/01/22
REPOSITORIES: GEO
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Project description:Background and aims: P53 limits the self-renewal of stem cells from various tissue. A Loss of p53 in combination with other oncogenic events results in aberrant self-renewal and transformation of progenitor cells. Here, we investigated whether a loss of p53 as a single genetic lesion is sufficient to induce liver tumor formation. Methods: AlfpCre mice were crossed with Trp53 conditional knockout mice to achieve a liver-specific loss of Trp53. Results: The liver-specific loss of Trp53 results in liver tumor formation. A high percentage of the tumors showed a mixed differentiation of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Conclusion: The liver-specific deletion of Trp53 is sufficient to induce liver tumor formation.
2021-01-22 | GSE156253 | GEO
Project description:Background and Aims: p53 can limit the self-renewal of stem cells from various tissues. Experimental evidence suggests that deletion of p53 can cooperate with other oncogenic events to induce aberrant self-renewal and transformation of progenitor cells. It is not known whether p53 deletion alone can lead to liver tumor formation. Methods: We used AlfpCre mice for liver-specific deletion of Trp53 in a conditional knockout mouse model to analyze liver carcinogenesis. Results: Here, we show that liver-specific deletion of p53 in mice consistently induces formation of liver carcinoma depicting bilineal differentiation. Freshly isolated p53-/- liver progenitor cells and hepatocytes exhibit chromosomal imbalances and an enhanced clonogenic capacity compared to p53-positive cells or p21-deficient cells. Primary cultures of hepatocytes and liver progenitor cells from p53-/- mice formed tumors with bilineal differentiation when transplanted into immuno-compromised mice. Together, these results indicate that loss of p53 alone is sufficient to induce primary liver cancer with bilineal differentiation originating from chromosomal instable cultured liver progenitor cells or hepatocytes. Conclusions: The study shows that p53-dependent checkpoints inhibit transformation of liver progenitor cells and hepatocytes involving p21-independent mechanisms. Liver tumors derived from Trp53 KO mice, liver tumors from DEN-treated wildtype mice, Trp53 KO liver and wildtype liver were isolated and RNA was extracted. Agilent-026655 Mouse 4x44K v2 arrays were used.
2011-12-29 | E-GEOD-34760 | biostudies-arrayexpress
Project description:Background and Aims: p53 can limit the self-renewal of stem cells from various tissues. Experimental evidence suggests that deletion of p53 can cooperate with other oncogenic events to induce aberrant self-renewal and transformation of progenitor cells. It is not known whether p53 deletion alone can lead to liver tumor formation. Methods: We used AlfpCre mice for liver-specific deletion of Trp53 in a conditional knockout mouse model to analyze liver carcinogenesis. Results: Here, we show that liver-specific deletion of p53 in mice consistently induces formation of liver carcinoma depicting bilineal differentiation. Freshly isolated p53-/- liver progenitor cells and hepatocytes exhibit chromosomal imbalances and an enhanced clonogenic capacity compared to p53-positive cells or p21-deficient cells. Primary cultures of hepatocytes and liver progenitor cells from p53-/- mice formed tumors with bilineal differentiation when transplanted into immuno-compromised mice. Together, these results indicate that loss of p53 alone is sufficient to induce primary liver cancer with bilineal differentiation originating from chromosomal instable cultured liver progenitor cells or hepatocytes. Conclusions: The study shows that p53-dependent checkpoints inhibit transformation of liver progenitor cells and hepatocytes involving p21-independent mechanisms.
2011-12-29 | GSE34760 | GEO
Project description:Background and Aims: Analysis of aging-induced impairments in satellite cells (SCs) – the stem cells of skeletal muscle that are required for its regeneration. Hox genes are known to control stem cell function and development of various tissues. Methods: We used AlfpCre mice for liver specific deletion of Trp53 in a conditional knockout mouse model to analyze liver carcinogenesis. Results: Here, we show that liver-specific deletion of p53 in mice consistently induces formation of liver carcinoma depicting bilineal differentiation. Freshly isolated p53-/- liver progenitor cells and hepatocytes exhibit chromosomal imbalances and an enhanced clonogenic capacity compared to p53-positive cells or p21-deficient cells. Primary cultures of hepatocytes and liver progenitor cells from p53-/- mice formed tumors with bilineal differentiation when transplanted into immuno-compromised mice. Together, these results indicate that loss of p53 alone is sufficient to induce primary liver cancer with bilineal differentiation originating from chromosomal instable cultured liver progenitor cells or hepatocytes. Conclusions: The study shows that p53-dependent checkpoints inhibit transformation of liver progenitor cells and hepatocytes involving p21-independent mechanisms. In this study the function of the Hoxa9 was analyzed in murine satellite cells.
2016-11-30 | GSE87811 | GEO
Project description:We used an experimental mouse model to further evaluate whether constitutive p53 deficiency in the germ line may increase the rate of de novo CNV in the offspring. C57Bl6 mice with defined trp53 status (either +/+, +/- or -/-) were crossed with 129SvSL trp53+/+ mice and 129SvSL trp53-/- mice were crossed with C57Bl6 trp53+/+ mice. CNV were analyzed in DNA isolated from whole F1 embryos at 17.5 days and compared with liver DNA from their parents. One out of 36 embryo from trp53+/+ parents was detected to have a potential de novo CNV. No de novo CNV was detected in 84 embryos with a p53 deficient parent. These observations suggest that, in this mouse model, partial or complete deficiency of p53 function in the germ line does not increase the rate of CNV formation in the offspring. Affymetrix Mouse Diversity Genotyping Array was performed at The Jackson Lab
2014-09-29 | E-GEOD-61660 | biostudies-arrayexpress
Project description:We used an experimental mouse model to further evaluate whether constitutive p53 deficiency in the germ line may increase the rate of de novo CNV in the offspring. C57Bl6 mice with defined trp53 status (either +/+, +/- or -/-) were crossed with 129SvSL trp53+/+ mice and 129SvSL trp53-/- mice were crossed with C57Bl6 trp53+/+ mice. CNV were analyzed in DNA isolated from whole F1 embryos at 17.5 days and compared with liver DNA from their parents. One out of 36 embryo from trp53+/+ parents was detected to have a potential de novo CNV. No de novo CNV was detected in 84 embryos with a p53 deficient parent. These observations suggest that, in this mouse model, partial or complete deficiency of p53 function in the germ line does not increase the rate of CNV formation in the offspring.
2014-09-29 | GSE61660 | GEO
Project description:Loss of p53 is considered to allow progression of colorectal tumors from the adenoma to the carcinoma stage. Using mice with an intestinal epithelial cell (IEC) specific deletion of p53, we demonstrate that single loss of p53 is not sufficient to initiate intestinal tumorigenesis, but markedly enhances carcinogen-induced tumor incidence and leads to invasive cancer and lymph node metastasis. While during the initiation stage p53 controls DNA damage and IEC survival, during tumor progression, loss of p53 is associated with the formation of an inflammatory microenvironment and activation of NF-kB and Stat3. Thus, we propose a novel p53 controlled tumor suppressive function that is independent of its well-established role in cell cycle regulation, apoptosis and senescence. 4 AOM induced cancers derived from Tp53DEIC mice were isolated and DNA was extracted. These were compared to genomic DNA isolated from healthy littermate control animals. Agilent Mouse 4x180K arrays were used (Design ID 27411).
2011-03-23 | E-GEOD-28129 | biostudies-arrayexpress
Project description:Background & Aims: Combined HCC-iCCA is a rare liver tumor type and is often not well separated from HCC and iCCA. In this study, we analyzed major differences between combined HCC-iCCA and iCCA. Methods: We first characterized major differences between combined HCC-iCCA and iCCA by GSEA analysis. Consequently, we used CCl4 to induce chronic liver disease and subsequent liver carcinoma formation in mice. We forced the formation of combined HCC-iCCA through liver specific deletion of Rbpj, a key component of the Notch signaling pathway, in a Trp53 deficient background. Notch and p53 signaling pathways are involved in cellular differentiation processes and belong to the most affected pathways in liver carcinogenesis. Results: We show that combined HCC-iCCA can be separated from iCCA through differences in development related pathways, metabolism, cell to cell interaction and immune related pathways in human patients and in mice. Dysregulation of Notch signaling through a hepatocyte-specific Rbpj knockout resulted in an increased tumor burden and a high frequency of combined HCC-iCCA formation. In addition, hepatocytic loss of Rbpj forced M2 macrophage polarization and a tumor promoting environment. Conclusions: Dysregulation of Notch signaling is involved in tumor differentiation. Loss of Rbpj triggers the formation of combined HCC-iCCA which is associated by a pro-tumorigenic environment. Our study highlights the importance of dysfunctional Notch signalling through Rbpj deletion in hepatocytes. Rbpj loss affects tumor differentiation and the tumor microenvironment which can be linked to a combined HCC-iCCA phenotype seen in human patients.
2023-08-31 | GSE212095 | GEO
Project description:Cell lines geneticially engineered to undergo conditional asymmetric self-renewal were used to identify genes whose expression is asymmetric self-renewal associated (ASRA). Non-random sister chromatid segregation occurs concordantly with asymmetric self-renewal in these cell lines. Asymmetric self-renewal occurs when murine embryo fibroblasts that are otherwise p53-null are induced to express physiological levels of wildtype p53 protein (Asym). To distinguish p53-responsive genes that also require induction of asymmetric self renewal (i.e., ASRA genes) and/or non-random sister chromatid segregation for change, an additional control cell line, which continues to symmetrically self-renew (with random sister chromatid segregation) even when p53 is induced, was also compared (Symp53). This congenic cell line constitutively expresses the type II inosine monophosphate dehydrogenase (IMPDH II; the rate-limiting enzmye for guanine ribonucleotide biosynthesis) and, thereby, prevents p53-induced asymmetric self-renewal and non-random sister chromatid segregation. Three biological replicates of asymmetrically self-renewing cultures (Asym1-3) were compared with cultures that were symmetrically self-renewing - either because they did not express p53 (3 biological replicates, Sym1-3) or they expressed constitutive IMPDH II (i.e., not regulated by p53) as well as p53 (2 biological replicates, Symp53_1 and 2.)
2010-12-22 | E-GEOD-25334 | biostudies-arrayexpress
Project description:Loss of p53 is considered to allow progression of colorectal tumors from the adenoma to the carcinoma stage. Using mice with an intestinal epithelial cell (IEC) specific deletion of p53, we demonstrate that single loss of p53 is not sufficient to initiate intestinal tumorigenesis, but markedly enhances carcinogen-induced tumor incidence and leads to invasive cancer and lymph node metastasis. While during the initiation stage p53 controls DNA damage and IEC survival, during tumor progression, loss of p53 is associated with the formation of an inflammatory microenvironment and activation of NF-kB and Stat3. Thus, we propose a novel p53 controlled tumor suppressive function that is independent of its well-established role in cell cycle regulation, apoptosis and senescence.
2011-03-24 | GSE28129 | GEO