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Loss of p53 in enterocytes facilitates an inflammatory microenvironment enabling invasion and metastasis of carcinogen-induced colorectal tumors

ABSTRACT: Here, we examined the role of intestinal epithelial specific tumor suppressive function of 53. We provide evidence that p53 plays a dual role during carcinogen-induced tumorigenesis. At the initiation stage, p53 controls DNA damage and survival of initiated epithelia. In contrast, at later stages, loss of p53 is associated with the formation of an inflammatory microenvironment that is linked to epithelial mesenchymal transition, invasion and metastasis and the activation of NF-kappaB and Stat3. Thus, we propose a novel p53 controlled tumor suppressive function during the progression stage of colorectal cancer that is independent of its well-established role in cell cycle regulation, apoptosis and senescence.

ORGANISM(S): Mus musculus

PROVIDER: GSE27868 | GEO | 2012/11/13

SECONDARY ACCESSION(S): PRJNA138017

REPOSITORIES: GEO

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Loss of p53 in enterocytes facilitates an inflammatory microenvironment enabling invasion and metastasis of carcinogen-induced colorectal tumors

Project description:Here, we examined the role of intestinal epithelial specific tumor suppressive function of 53. We provide evidence that p53 plays a dual role during carcinogen-induced tumorigenesis. At the initiation stage, p53 controls DNA damage and survival of initiated epithelia. In contrast, at later stages, loss of p53 is associated with the formation of an inflammatory microenvironment that is linked to epithelial mesenchymal transition, invasion and metastasis and the activation of NF-kappaB and Stat3. Thus, we propose a novel p53 controlled tumor suppressive function during the progression stage of colorectal cancer that is independent of its well-established role in cell cycle regulation, apoptosis and senescence. 6 samples were analyzed. We compared 3 wt colon tumor samples and 3 p53-knockout tumor samples.

2012-11-13 | E-GEOD-27868 | biostudies-arrayexpress

Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and metastasis of carcinogen-induced colorectal tumors

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

Loss of p53 in enterocytes generates an inflammatory microenvironment enabling invasion and metastasis of carcinogen-induced colorectal tumors

2011-03-23 | E-GEOD-28129 | biostudies-arrayexpress

Early anti-tumor activity of oral Langerhans cells is compromised by a carcinogen

Project description:Early diagnosis of oral squamous cell carcinoma (OSCC) remains an unmet clinical need. Therefore, elucidating the initial events of OSCC preceding tumor development could benefit OSCC prognosis. Here we define the Langerhans cells (LC) of the tongue and demonstrate that LC protect the epithelium from carcinogen-induced OSCC by rapidly priming αβT cells capable of eliminating γH2AX+ epithelial cells, whereas γδT and NK cells are dispensable. The carcinogen, however, dysregulates the epithelial resident mononuclear phagocytes, reducing LC frequencies while dendritic cells (DC), macrophages, and plasmacytoid DC (pDC) populate the epithelium. Single-cell RNAseq analysis indicates that these newly differentiated cells display an immunosuppressive phenotype accompanied by an expansion of T regulatory (Treg) cells. Accumulation of the Treg cells was regulated, in part, by pDC and precedes the formation of visible tumors. This suggests LC play an early protective role during OSCC, yet the capacity of the carcinogen to dysregulate the differentiation of mononuclear phagocytes facilitates oral carcinogenesis.

2022-01-26 | GSE192470 | GEO

UV-induced DNA lesion mapping reveals that carcinogen susceptibility is regulated by genome architecture and dictates cancer mutagenesis

Project description:In this study, we present the first quantitative human genome-wide map of DNA lesions induced by ultraviolet (UV) radiation, the ubiquitous carcinogen in sunlight that causes skin cancer. Remarkably, the pattern of carcinogen susceptibility across the genome of primary cells significantly reflects mutation frequency in malignant melanoma. Surprisingly, DNase-accessible euchromatin is protected from UV, while lamina-associated heterochromatin at the nuclear periphery is vulnerable. Many cancer driver genes have an intrinsic increase in carcinogen susceptibility, including the BRAF oncogene that has the highest mutation frequency in melanoma. These findings provide a genome-wide snapshot of DNA injuries in cells at the earliest stage of carcinogenesis. Furthermore, they identify carcinogen susceptibility as a previously unrecognized origin of mutagenesis that is regulated by nuclear architecture and dictates genome instability in cancer.

2017-08-12 | GSE94434 | GEO

Acute Effects Caused by the Rodent Non-Genotoxic Carcinogen Diethylhexylphthalate

Project description:Acute effects caused by the non-genotoxic carcinogen and peroxisome proliferator (PP) diethylhexylphthalate (DEHP) in the mouse liver

2014-03-17 | GSE55733 | GEO

Acute Effects Caused by the Rodent Non-Genotoxic Carcinogen Diethylhexylphthalate

Project description:Acute effects caused by the non-genotoxic carcinogen and peroxisome proliferator (PP) diethylhexylphthalate (DEHP) in the mouse liver Mice (n = 6) were dosed by oral gavage (10 ml/kg body weight) with the non-genotoxic carcinogen diethylhexylphthalate (DEHP), every 24 h for 3 days (1150 mg/kg/day), or with an equivalent volume of vehicle control (corn oil).

2014-03-17 | E-GEOD-55733 | biostudies-arrayexpress

Lipopolysaccharide-mediated chronic inflammation promotes tobacco carcinogen-induced lung tumorigenesis

Project description:We developed a two-staged lung cancer mouse model, which mimics the smoking carcinogen-induced, and chronic obstructive pulmonary disease (COPD)-related airway inflammation promoted lung cancers. We used the carcinogen 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK) to induce lung cancer and in parallel to repeated Lipopolysaccharide (LPS) installation to induce chronic lung inflammation. To identify genes associated with chronic inflammation promoting lung tumorigenesis, we have performed whole genome microarray expression profiling of mice exposed to Phosphate-Buffered Saline (PBS), NNK, LPS, and combined NNK and LPS.

2020-12-31 | GSE132661 | GEO

RNAseq carcinogen induced signatures in lung adenocarcinoma cell lines

Project description:FVB, Balb/c, and C57BL/6 mice received the tobacco carcinogens urethane (Sigma Aldrich, U2500) intraperitoneally (1g/Kg in 100 μl phosphate-buffered saline) or diethylnitrosamine (200 mg/kg) (Sigma Aldrich, N0756). Carcinogen induced lung adenocarcinoma murine cell lines generation| Ten months post first carcinogen (urethane, DEN) exposure mice were sacrificed, lung tumours were dissected from surrounding healthy lung parenchyma under sterile conditions, were halved, one half was processed for histology and the other half was chopped into 1 mm pieces and seeded to cell culture dishes. Cells were cultured under standard conditions outlined below. When adenocarcinoma was diagnosed for a given tumour, its corresponding culture was passaged in vitro over a period of 18 months and 60 passages, whichever occurred first. After gene expression and mutational signature extraction, the signature were compared with human lung adenocarcinoma RNAseq results.

2022-10-24 | GSE126119 | GEO

Suppression of p53-mediated senescence by non-canonical NF-kappaB pathway mediated regulation of EZH2 expression

Project description:The NF-kappaB and p53 transcription factors control the expression of complex gene regulatory networks in response to many cell stresses and stimuli. This experiment describes gene expression profiling of cells depleted for EZH2, NF-kappaB2, RelB and p53. We find that EZH2 is the major effector of crosstalk between the alternative NF-kappaB and p53 pathways and acts to suppress cellular senescence. Total RNA was obtained from primary juvenile human dermal fibroblasts 48 hours after transfection with siRNA specific for one, or a targeted combination of the transcription factors, or a scrambled siRNA control.

2014-03-31 | E-MTAB-1593 | biostudies-arrayexpress

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