Hoxa13 overexpression drives chromosomal instability and liver tumorigenesis in mice
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PROVIDER: PRJNA700569 | ENA |
REPOSITORIES: ENA
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Project description:Background and aims: Class I Homeobox (HOX) genes are fundamental components of embryonic patterning and morphogenesis, also implicated in neoplastic transformations. Among them HOXA13, in particular, has been found to be the most overexpressed in HCC and to be associated with worse prognosis. However, no previous work has shown so far a direct causal effect between HOXA13 overexpression and liver tumorigenesis. In this study we aimed to prove the direct oncogenicity of HOXA13 in the liver and to unravel the molecular mechanisms of Hoxa13-induced liver tumorigenesis. Approach and Results: To unravel the oncogenic mechanism of HOXA13 in vivo, a transgenic mouse model of HOXA13 overexpression in the liver was generated using hydrodynamic tail vein injection coupled with a transposase system. The mice phenotype was followed over time, from 2 weeks up to 1-year post injection. RNA-sequencing was performed to monitor the transcriptomic changes over time. HOXA13-overexpression in the liver led to highly proliferative hepatocytes and correlated with the DNA damage marker yH2AX. 1-year post-injection 50% of the injected mice developed liver tumors of various histological grades and types. RNA-sequencing analysis performed on whole liver extracts of 2 weeks-old mice and tumors showed that the main pathway deregulated by HOXA13 overexpression was cell cycle, in particular G2/M transition and mitotic spindle assembly checkpoint. Additionally, HOXA13-overexpressing livers showed a transcriptomic signature of chromosomal Instability, suggesting a possible mechanism of tumorigenesis driven by genome instability. Conclusions: Our study highlights the role of HOXA13 as a novel oncogenic driver in hepatocarcinogenesis and strongly suggests that its oncogenic properties are least partially mediated by induction of chromosomal instability.
2021-02-09 | GSE166341 | GEO
Project description:Degree and site of chromosomal instability define its role in tumorigenesis
| PRJEB31573 | ENA
Project description:Chromosomal instability (CIN) is thought to be a source of mutability in human cancer. However, CIN is highly deleterious for the cell, and the resulting aneuploidy induces metabolic stress and compromises cell fitness. Here we utilized the X-chromosome dosage compensation mechanism and changes in X-chromosome number to demonstrate in Drosophila epithelial cells the causal relationship between CIN, aneuploidy, gene dosage imbalance and tumorigenesis. Whereas the harmful effects of CIN can be buffered by resetting the X-chromosome dosage compensation to compensate for changes in X-chromosome number, interfering with the mechanisms of dosage compensation suffices to induce tumorigenesis. In addition, multiple mechanisms buffer the deleterious effects of CIN including DNA-damage repair, activation of the p38 signalling pathway, and induction of cytokine expression to promote compensatory cell proliferation. These data reveal a key role of gene dosage imbalances to CIN-induced programmed cell death and tumorigenesis and the existence of robust compensatory mechanisms.
2016-05-23 | GSE71242 | GEO
Project description:Transient genomic instability drives tumorigenesis through accelerated clonal evolution
| PRJNA679266 | ENA
Project description:The Caspase-Activated DNAse drives chromosomal instability and cancer metastasis
| PRJNA649945 | ENA
Project description:Background and Aims: Telomere dysfunction can increase tumor initiation by induction of chromosomal instability, but initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. However, this concept has not been proven in vivo since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis (i) in a novel mouse model of inducible telomere dysfunction on a telomerase-proficient background, (ii) in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and (iii) in wild-type mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation and cancer cell proliferation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell cycle arrest and apoptosis in telomerase-deficient liver tumors. Together, these data provide the first in vivo evidence that transient telomere dysfunction during early and late stages of tumorigenesis can promote chromosomal instability and carcinogenesis in telomerase-proficient mice in the absence of additional genetic checkpoint defects at germline level.
2012-03-31 | GSE36813 | GEO
Project description:Background and Aims: Telomere dysfunction can increase tumor initiation by induction of chromosomal instability, but initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. However, this concept has not been proven in vivo since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis (i) in a novel mouse model of inducible telomere dysfunction on a telomerase-proficient background, (ii) in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and (iii) in wild-type mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation and cancer cell proliferation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell cycle arrest and apoptosis in telomerase-deficient liver tumors. Together, these data provide the first in vivo evidence that transient telomere dysfunction during early and late stages of tumorigenesis can promote chromosomal instability and carcinogenesis in telomerase-proficient mice in the absence of additional genetic checkpoint defects at germline level. RNA from liver tumors derived from from DEN treated TTD+ mice TTD- mice and RNA from normal liver 48h-72h after doxycycline induced transient telomere dysfunction in TTD+ and TTD- liver were isolated and RNA was extracted. Agilent Mouse 4x44K v2 arrays were used. DNA from liver tumors and corrresponding kidney as control derived from from DEN treated TTD+ mice, TTD- mice and mTERC-/- G3 mice was isolated and extracted using Phenol/Chloroform. Agilent Mouse 4x44K and Mouse 1x244K arrays were used.
2012-03-30 | E-GEOD-36813 | biostudies-arrayexpress
Project description:Oxidative DNA damage is likely to be involved in the etiology of cancer and is thought to accelerate tumorigenesis via increased mutation rates. However, the majority of malignant cells acquire a specific type of genomic instability characterized by large-scale genomic rearrangements, defined as chromosomal instability (CIN). The molecular mechanisms underlying CIN are largely unknown. We utilized Saccharomyces cerevisiae as a model system to delineate the relationship between genotoxic stress and CIN. It was found that elevated levels of chronic, unrepaired oxidative DNA damage cause chromosomal aberrations at remarkably high frequencies under both selective and non-selective growth conditions. In this system, exceeding the cellular capacity to appropriately manage oxidative DNA damage results in a “gain of CIN” phenotype and leads to profound karyotypic diversification. These results illustrate a novel mechanism for genome destabilization, which is likely to be relevant to human carcinogenesis. Keywords: CGH-array
2008-02-10 | GSE10152 | GEO
Project description:The goal of the experiment was to determine HOXA13 binding loci in human melanoma cells to infer downstream targets of a HOXA13 positional program.
2022-01-17 | GSE181768 | GEO
Project description:We explored the role of CCAT2 in inducing chromosomal instability in gastrointestinal cancers.
2020-06-01 | GSE133590 | GEO