Project description:To determine how gene expression varies between fast and slow proliferating cells we developed a CFSE-based method to sort cells by intrapopulation heterogeneity in proliferation rate. We sorted cells by proliferation rate, as well as by the mitochondria dye TMRE, and performed mRNA-seq.
Project description:CDH3 is a single-span transmembrane domain glycoprotein that mediates cell-cell adhesion. It is normally expression in basal cells, luminal epithelial cells and monocytes of lung airway epithelial cells. However, the CDH3 gene is also frequently overexpressed in many cancers. Expression of CDH3 is an indicator of poor prognosis in human breast cancer and a marker for real-time monitoring of resistance to first/second generation EGFR-TKIs. In this present manuscript, we describe that high CDH3 expression is correlated with shorter overall survival of patients in lung adenocarcinomas and low CDH3 expression inhibits cells’ proliferation and migration
Project description:Mueller2015 - Hepatocyte proliferation, T160
phosphorylation of CDK2
This model is described in the article:
T160-phosphorylated CDK2
defines threshold for HGF-dependent proliferation in primary
hepatocytes.
Mueller S, Huard J, Waldow K, Huang
X, D'Alessandro LA, Bohl S, Börner K, Grimm D, Klamt S,
Klingmüller U, Schilling M.
Mol. Syst. Biol. 2015; 11(3): 795
Abstract:
Liver regeneration is a tightly controlled process mainly
achieved by proliferation of usually quiescent hepatocytes. The
specific molecular mechanisms ensuring cell division only in
response to proliferative signals such as hepatocyte growth
factor (HGF) are not fully understood. Here, we combined
quantitative time-resolved analysis of primary mouse hepatocyte
proliferation at the single cell and at the population level
with mathematical modeling. We showed that numerous G1/S
transition components are activated upon hepatocyte isolation
whereas DNA replication only occurs upon additional HGF
stimulation. In response to HGF, Cyclin:CDK complex formation
was increased, p21 rather than p27 was regulated, and Rb
expression was enhanced. Quantification of protein levels at
the restriction point showed an excess of CDK2 over CDK4 and
limiting amounts of the transcription factor E2F-1. Analysis
with our mathematical model revealed that T160 phosphorylation
of CDK2 correlated best with growth factor-dependent
proliferation, which we validated experimentally on both the
population and the single cell level. In conclusion, we
identified CDK2 phosphorylation as a gate-keeping mechanism to
maintain hepatocyte quiescence in the absence of HGF.
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Project description:Using our unique and authentic animal model, the pig, we determined which genes in the normal mammary gland are regulated in response to different combinations of the ovarian hormones estrogen and progesterone and the pituitary hormone prolactin. We surgically removed ovaries from 32 pigs to deplete endogenous estrogen and progesterone, and administered bromocriptine to suppress endogenous prolactin. Pigs were treated with all combinations of estrogen, progesterone and bromocriptine and/or haloperidol (to induce prolactin secretion), in a factorial design. Affymetrix arrays were used to analyze RNA from the mammary glands of these pigs and we found that estrogen, prolactin and the interaction of estrogen*prolactin were the primary regulators of gene expression in the mammary gland. This is in contrast to rodents where progesterone has an important role in ductal elongation and branching. Functional enrichment analyses suggest that estrogen promotes cell division while prolactin stimulates elements of fatty acid metabolism and an inflammatory response (in addition to milk protein genes). These results concur with phenotypic changes where estrogen, prolactin and estrogen*prolactin were the most important regulators of morphological development, cell proliferation and steroid receptor expression. Regression analysis of expression data against the rate of cell proliferation in all 32 pigs identified 1669 genes correlated with proliferation (FDR a=0.01). Regression analysis of expression data against proliferation in the 16 pigs treated with E identified 71 genes correlated with proliferation. 29 genes were common to both lists and also regulated by estrogen, and of these 16 have known functions in the cell cycle while the other 13 have never been associated with estrogen regulated mammary gland growth or cell proliferation. Twenty six of these genes were more highly correlated with proliferation than MKI67 (Ki67).
Project description:Recent studies have shown that high cell cycle activity negatively correlates with antitumor immunity in certain cancer types. However, a similar correlation has not been proven in liver cancer.We downloaded transcriptomic profiles of TCGA-LIHC (the cancer genome atlas-liver hepatocellular carcinoma) and assessed the cell cycle distribution of samples using single sample gene set enrichment analysis (ssGSEA), termed the cell cycle score (CCS). We obtained cell cycle-related differentially expressed prognostic genes and identified CENPA, CDC20 and CTSV using LASSO regression. We studied the effect of CTSV on clinical features and immune alterations in liver cancer based on TCGA-LIHC data. In vitro and in vivo experiments were performed to validate the role of CTSV in liver cancer using liver cancer cell lines and tissues.We found that the CCS closely correlated with the clinical features and prognosis of patients in TCGA-LIHC. Analysis of differentially expressed genes (DEGs), univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression identified cathepsin V (CTSV) with prognostic significance in LIHC. Importantly, single-gene survival analysis of CTSV using microarray and sequencing data indicated that high levels of CTSV expression correlated with an unfavorable prognosis in various cancers. Gene set enrichment analysis (GSEA) revealed that high CTSV expression closely correlated with decreased expression of metabolic genes and increased expression of cell cycle genes. Furthermore, difference and correlation analyses of the relationship between CTSV expression and immune infiltrates, determined using CIBERSORT and TIMER algorithms, revealed that CTSV expression correlated with macrophages and CD4+ T cells. In vitro and in vivo experiments revealed that knockdown of CTSV inhibited liver cancer cells proliferation. Immunohistochemical staining showed that high CTSV expression correlated with macrophage infiltration in liver cancer tissues, predicted a poor prognosis, and may serve as a biomarker for HCC therapy.In conclusion, CTSV is a novel cell cycle prognostic gene that can affect HCC cells proliferation, and a potential biomarker for HCC therapy.
Project description:This SuperSeries is composed of the following subset Series: GSE41751: Correlated alterations in genome organization, histone methylation, and DNA-lamina interactions in Hutchinson-Gilford progeria syndrome (expression) GSE41757: Correlated alterations in genome organization, histone methylation, and DNA-lamina interactions in Hutchinson-Gilford progeria syndrome (ChIP-seq) GSE41763: Correlated alterations in genome organization, histone methylation, and DNA-lamina interactions in Hutchinson-Gilford progeria syndrome (Hi-C) Refer to individual Series
Project description:Bladder cancer (BC) is one of the most common cancers in the world. T-cell immunoglobulin and mucin domain 1 (TIM-1) are involved in the progression of multiple tumors. However the role of TIM-1 in BC progression is poorly understood. In this study, we searched the Gene Expression Profiling Interactive Analysis (GEPIA) database and performed immunohistochemistry (IHC) to assess TIM-1 protein expression in bladder cancer (BC) patients. The results demonstrated that BC with high TIM-1 expression was associated with longer overall survival (OS) and disease-specific survival (DSS) than BC with low TIM-1 expression. Overexpression of TIM-1 inhibits BC cell proliferation in both cell culture and animal experiments. RNA sequencing data indicated that interferon-induced protein with tetratricopeptide repeats (IFIT) genes induced by interferon-α (IFN-α) were significantly enriched among the genes upregulated by TIM-1 overexpression. Mechanistically, our data revealed that TIM-1 promotes IFN-α release and activates the IFIT2/p-STAT1 pathway, which is known to be related to tumor cell proliferation. Moreover, knockdown of IFIT2 in TIM-1-overexpressing BC cells hinders the tumor suppressive effect of TIM-1. Our results revealed that TIM-1 is a potential molecular marker for BC prognosis and indicate that high TIM-1 expression suppresses BC cell proliferation in an IFIT2/p-STAT1-dependent manner.