EGFR Induces E2F1-Mediated Corticotroph Tumorigenesis.
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ABSTRACT:
SUBMITTER: Araki T
PROVIDER: S-EPMC5686559 | biostudies-literature | 2017 Feb
REPOSITORIES: biostudies-literature
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Project description:Epidermal growth factor receptor (EGFR) signaling is a known mediator of colorectal carcinogenesis. Studies have focused on the role of EGFR signaling in epithelial cells, although the exact nature of the role of EGFR in colorectal carcinogenesis remains a topic of debate. Here, we present evidence that EGFR signaling in myeloid cells, specifically macrophages, is critical for colon tumorigenesis in the azoxymethane-dextran sodium sulfate (AOM-DSS) model of colitis-associated carcinogenesis (CAC). In a human tissue microarray, colonic macrophages demonstrated robust EGFR activation in the pre-cancerous stages of colitis and dysplasia. Utilizing the AOM-DSS model, mice with a myeloid-specific deletion of Egfr had significantly decreased tumor multiplicity and burden, protection from high-grade dysplasia and significantly reduced colitis. Intriguingly, mice with gastrointestinal epithelial cell-specific Egfr deletion demonstrated no differences in tumorigenesis in the AOM-DSS model. The alterations in tumorigenesis in myeloid-specific Egfr knockout mice were accompanied by decreased macrophage, neutrophil and T-cell infiltration. Pro-tumorigenic M2 macrophage activation was diminished in myeloid-specific Egfr-deficient mice, as marked by decreased Arg1 and Il10 mRNA expression and decreased interleukin (IL)-4, IL10 and IL-13 protein levels. Surprisingly, diminished M1 macrophage activation was also detectable, as marked by significantly reduced Nos2 and Il1b mRNA levels and decreased interferon (IFN)-?, tumor necrosis factor (TNF)-? and IL-1? protein levels. The alterations in M1 and M2 macrophage activation were confirmed in bone marrow-derived macrophages from mice with the myeloid-specific Egfr knockout. The combined effect of restrained M1 and M2 macrophage activation resulted in decreased production of pro-angiogenic factors, CXCL1 and vascular endothelial growth factor (VEGF), and reduced CD31+ blood vessels, which likely contributed to protection from tumorigenesis. These data reveal that EGFR signaling in macrophages, but not in colonic epithelial cells, has a significant role in CAC. EGFR signaling in macrophages may prove to be an effective biomarker of CAC or target for chemoprevention in patients with inflammatory bowel disease.
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Project description:Cushing's disease is caused by pituitary corticotroph adenoma, and the pathogenesis of it has remained obscure. Here, we showed that cold inducible RNA binding protein (CIRP) was markedly elevated in corticotroph tumors. Forced overexpression of CIRP in murine AtT20 pituitary corticotroph cell line increased corticotroph precursor hormone proopiomelanocortin (POMC) transcription, ACTH secretion and cellular proliferation. In vivo, CIRP overexpression promotes murine corticotroph tumor growth and enhances ACTH production. Mechanistically, we show that CIRP could promote AtT20 cells proliferation by inducing cyclinD1 and decreasing p27 expression via Erk1/2 signaling pathway. Clinically, CIRP overexpression is significantly correlated with Cushing's disease recurrence. CIRP appears to play a critical tumorigenesis function in Cushing's disease and its expression might be a useful biomarker for tumor recurrence.
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Project description:Backgroundp53 induces cell-cycle arrest and apoptosis in cancer cells and negatively regulates glycolysis via TIGAR. Glycolysis is crucial for cancer progression although TIGAR provides protection from reactive oxygen species and apoptosis. The relation between TIGAR-mediated inhibition of glycolysis and p53 tumour-suppressor activity is unknown.MethodsRT-PCR, western blot, luciferase and chromatin immunoprecipitation assays were used to study TIGAR gene regulation. Co-IPP was used to determine the role of TIGAR protein in regulating the protein-protein interaction between retinoblastoma (RB) and E2F1. MCF-7 tumour xenografts were utilised to study the role of TIGAR in tumour regression.ResultsOur study shows that TIGAR promotes p21-independent, p53-mediated G1-phase arrest in cancer cells. p53 activates the TIGAR promoter only in cells exposed to repairable doses of stress. TIGAR regulates the expression of genes involved in cell-cycle progression; suppresses synthesis of CDK-2, CDK-4, CDK-6, Cyclin D, Cyclin E and promotes de-phosphorylation of RB protein. RB de-phosphorylation stabilises the complex between RB and E2F1 thus inhibiting the entry of cell cycle from G1 phase to S phase.ConclusionTIGAR mediates de-phosphorylation of RB and stabilisation of RB-E2F1 complex thus delaying the entry of cells in S phase of the cell cycle. Thus, TIGAR inhibits proliferation of cancer cells and increases drug-mediated tumour regression by promoting p53-mediated cell-cycle arrest.
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Project description:Objective: Epidermal growth factor receptor (EGFR) has been found to localize in several human neoplasms and has been shown to have a significant correlation with adenomaigenesis and patient prognosis. EGFR is also overexpressed in pituitary corticotroph adenomas. However, its clinical significance and relationship with tumor behavior, especially tumor recurrence status, remain obscure. The purpose of the present study was to identify the expression patterns of EGFR and its downstream signaling pathway molecules in pituitary corticotroph adenomas and to investigate the association of EGFR with clinicopathological characteristics and tumor recurrence. Methods: Fifty-two sporadic pituitary adenoma specimens and six normal pituitary glands were collected. The expression levels of EGFR and its downstream signaling molecules in each sample were evaluated and quantified using immunohistochemistry and Western blot. The relationships of EGFR expression with clinicopathological characteristics and tumor recurrence status were analyzed. Results: EGFR was overexpressed in 55.8% of the pituitary corticotroph adenomas and in 1 of 6 of the normal adenohypophysial tissues. The expression degree was significantly higher in pituitary corticotroph adenomas than in normal adenohypophysial tissues. In EGFR-overexpressing adenomas, the downstream pathway phosphorylated Erk (p-Erk) was also significantly activated. Moreover, the expression levels of EGFR were positively correlated with the adrenocorticotropic hormone (ACTH) and cortisol levels but were not correlated with age, sex or symptom duration. The expression levels of EGFR, phosphorylated EGFR (p-EGFR) and p-Erk were significantly up-regulated in the recurrent adenoma group compared with those in the non-recurrent adenoma group (all p < 0.05). The expression levels of EGFR were strongly correlated with the recurrence-free interval (p = 0.005, CC = -0.31). Conclusion: The expression levels of EGFR and its downstream pathway components were significantly increased in pituitary corticotroph adenomas compared to the levels in normal adenohypophysial tissues. EGFR expression levels were positively associated with the ACTH and cortisol levels and with tumor recurrence status. Pituitary corticotroph adenomas with high EGFR expression levels were correlated with an increased recurrence rate and a decreased recurrence-free interval. EGFR could be used as a promising biomarker for predicting pituitary corticotroph tumor recurrence.
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Project description:Deregulation of mitogen-activated protein kinase (MAPK) signaling leads to development of pancreatic cancer. Although Ras-mutation-driven pancreatic tumorigenesis is well understood, the underlying mechanism of Ras-independent MAPK hyperactivation remains elusive. Here, we have identified a distinct function of PCNA-associated factor (PAF) in modulating MAPK signaling. PAF is overexpressed in pancreatic cancer and required for pancreatic cancer cell proliferation. In mouse models, PAF expression induced pancreatic intraepithelial neoplasia with expression of pancreatic cancer stem cell markers. PAF-induced ductal epithelial cell hyperproliferation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation independently of Ras or Raf mutations. Intriguingly, PAF transcriptionally activated the expression of late endosomal/lysosomal adaptor, MAPK and mTOR activator 3 (LAMTOR3), which hyperphosphorylates MEK and ERK and is necessary for pancreatic cancer cell proliferation. Our results reveal an unsuspected mechanism of mitogenic signaling activation via LAMTOR3 and suggest that PAF-induced MAPK hyperactivation contributes to pancreatic tumorigenesis.
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Project description:Studies performed in the last two decades have identified microRNA (miR)-1298-5p to display tumor-suppressive functions in several types of malignancy. In addition, the regulatory role of E2F transcription factor 1 (E2F1) has been reported in multiple types of cancer, including breast cancer (BC). However, whether miR-1298-5p participates in BC progression and whether a regulatory association exists between miR-1298-5p and E2F1 remains to be explored. The present study aimed to determine the role of miR-1298-5p and its interaction with E2F1 in BC. The expression of miR-1298-5p and E2F1 was examined by reverse transcription-quantitative PCR and western blot assays. The viability and proliferative capacity of BC cells were evaluated by Cell Counting Kit-8 and 5-bromo-2'-deoxyuridine assays, respectively. The apoptotic rate was assessed by the caspase-3 activity assay and flow cytometry; the protein expression levels of vimentin and E-cadherin were evaluated by western blotting. In addition, the adhesive and migratory abilities of BC cells were determined by conducting cell adhesion and wound healing assay, respectively. The target relationship between miR-1298-5p and E2F1 was validated by the luciferase reporter assay. The results of the present study revealed that the levels of miR-1298-5p were downregulated in BC tissues and cells compared with those in normal breast tissues and cells, respectively. In addition, miR-1298-5p was demonstrated to inhibit the proliferation, adhesion and migration of BC cells and to promote BC cell apoptosis. E2F1 was verified as a target gene of miR-1298-5p using the luciferase reporter assay. Additionally, E2F1 exhibited an opposite expression pattern compared with that of miR-1298-5p in BC tissues. Furthermore, the downregulation of miR-1298-5p in BC cells was reversed by silencing E2F1. Overall, the results of the present study suggested that miR-1298-5p repressed BC cell proliferation, adhesion and migration, and enhanced BC cell apoptosis by downregulating E2F1.
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