Gene network analysis leads to functional validation of pathways linked to cancer cell growth and survival

Berger, Emmanuelle; Véga, Nathalie; Vidal, Hubert; Géloën, Alain

doi:10.1002/biot.201200188

Cited by 14 publications

(21 citation statements)

References 52 publications

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“…We previously developed a comparative analysis of gene dataset enrichment in order to identify signaling pathways significantly enriched in selected phenotypes. For example, we identified pathways related to adiponectin signaling in cancer cells [ 13 ], cell proliferation, and/or survival as well as the pathways involved in glucose signaling and specifically dysregulated in hepatocellular carcinoma [ 14 , 15 ]. Several of the merged pathways have been further experimentally validated, and most of them correspond to previously published data.…”

Section: Resultsmentioning

confidence: 99%

Oleic Acid Uptake Reveals the Rescued Enterocyte Phenotype of Colon Cancer Caco-2 by HT29-MTX Cells in Co-Culture Mode

Berger

Nassra

Atgié

et al. 2017

IJMS

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Gastrointestinal epithelium is the unique route for nutrients and for many pharmaceuticals to enter the body. The present study aimed to analyze precisely whether co-culture of two colon cancer cell lines, mucus-producing cells HT29-MTX and enterocyte-like Caco-2 cells, ameliorate differentiation into an in vitro intestinal barrier model and the signaling pathways involved. Differentiated Caco-2 cells gene datasets were compared first to intestinal or cancer phenotypes and second to signaling pathway gene datasets. Experimental validations were performed in real-time experiments, immunochemistry, and gene expression analyses on Caco-2 versus co-cultures of Caco-2 and HT29-MTX (10%) cells. Partial maintenance of cancer-cell phenotype in differentiated Caco-2 cells was confirmed and fatty acids merged as potential regulators of cancer signaling pathways. HT29-MTX cells induced morphological changes in Caco-2 cells, slightly increased their proliferation rate and profoundly modified gene transcription of phenotype markers, fatty acid receptors, intracellular transporters, and lipid droplet components as well as functional responses to oleic acid. In vitro, enterocyte phenotype was rescued partially by co-culture of cancer cells with goblet cells and completed through oleic acid interaction with signaling pathways dysregulated in cancer cells.

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Section: Resultsmentioning

confidence: 99%

Oleic Acid Uptake Reveals the Rescued Enterocyte Phenotype of Colon Cancer Caco-2 by HT29-MTX Cells in Co-Culture Mode

Berger

Nassra

Atgié

et al. 2017

IJMS

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“…Some of the targets are known oncoproteins, which includes EGFR [99], VEGFA [100], ZBTB7 (POKEMON) [101], acid phosphatase 2(ACP2) [102] and NFKB1 [103]. Additionally, proteins that are overexpressed in cancer cells are among the targets of down-regulated miRNAs in different treatment conditions, which includes Wnt3A [104], PPARα [105], UCP2 [106], CSF1 [107], and MED1 [108]. …”

Section: Resultsmentioning

confidence: 99%

MicroRNA expressions associated with progression of prostate cancer cells to antiandrogen therapy resistance

et al. 2014

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BackgroundDevelopment of resistance to androgen deprivation therapy (ADT) is a major obstacle for the management of advanced prostate cancer. Therapies with androgen receptor (AR) antagonists and androgen withdrawal initially regress tumors but development of compensatory mechanisms including AR bypass signaling leads to re-growth of tumors. MicroRNAs (miRNAs) are small regulatory RNAs that are involved in maintenance of cell homeostasis but are often altered in tumor cells.ResultsIn this study, we determined the association of genome wide miRNA expression (1113 unique miRNAs) with development of resistance to ADT. We used androgen sensitive prostate cancer cells that progressed to ADT and AR antagonist Casodex (CDX) resistance upon androgen withdrawal and treatment with CDX. Validation of expression of a subset of 100 miRNAs led to identification of 43 miRNAs that are significantly altered during progression of cells to treatment resistance. We also show a correlation of altered expression of 10 proteins targeted by some of these miRNAs in these cells.ConclusionsWe conclude that dynamic alterations in miRNA expression occur early on during androgen deprivation therapy, and androgen receptor blockade. The cumulative effect of these altered miRNA expression profiles is the temporal modulation of multiple signaling pathways promoting survival and acquisition of resistance. These early events are driving the transition to castration resistance and cannot be studied in already developed CRPC cell lines or tissues. Furthermore our results can be used a prognostic marker of cancers with a potential to be resistant to ADT.

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“…In a previous study, this method has been extensively depicted and led to characterize hepatocellular cancer cell phenotype in comparison to healthy liver. 29 In the present study, we raised a list of genes representative of human adipocyte lineage, called «human adipose» gene set ( Table 1), which is a result of gene sets representative of human adipose-derived stem cells (hASC gene set), human adipose cell differentiated in vitro (hdA, Differentiating gene set) and adipose tissues (TA gene set), respectively, i.e., genes specifically detected in comparison to non-adipose cell types. Cumulative data obtained in mouse were also retrieved, leading to «Mouse adipose» gene set.…”

Section: Resultsmentioning

confidence: 99%

“…Human liver gene set was obtained in a previous study. 29 KEGG pathways gene number counts 69 were performed to raise gene datasets representative of either phenotypes or data sets (Supplementary Data 2).…”

Section: Bio-informatic Analysesmentioning

confidence: 99%

“…32 Levels of target mRNAs were normalized to hypoxanthine phosphoribosyltransferase 1 (HPRT1) expression (sequence of primers are available in ref. 29 measured at least on 3 independent experiments and data are presented as mean § SD. Comparative analyzes were performed on a representative experiment in at least 4 replicates and significance was measured using ANOVA variance test.…”

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confidence: 99%

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Pathways commonly dysregulated in mouse and human obese adipose tissue: FAT/CD36 modulates differentiation and lipogenesis

et al. 2015

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Obesity is linked to adipose tissue hypertrophy (increased adipocyte cell size) and hyperplasia (increased cell number). Comparative analyses of gene datasets allowed us to identify 1426 genes which may represent common adipose phenotype in humans and mice. Among them we identified several adipocyte-specific genes dysregulated in obese adipose tissue, involved in either fatty acid storage (acyl CoA synthase ACSL1, hormone-sensitive lipase LIPE, aquaporin 7 AQP7, perilipin PLIN) or cell adhesion (fibronectin FN1, collagens COL1A1, COL1A3, metalloprotein MMP9, or both (scavenger receptor FAT/CD36). Using real-time analysis of cell surface occupancy on xCELLigence system we developed a new method to study lipid uptake and differentiation of mouse 3T3L1 fibroblasts and human adipose stem cells. Both processes are regulated by insulin and fatty acids such as oleic acid. We showed that fatty acid addition to culture media increased the differentiation rate and was required for full differentiation into unilocular adipocytes. Significant activation of lipogenesis, i.e. lipid accumulation, by either insulin or oleic acid was monitored in times ranging from 1 to 24 h, depending on differentiation state, whereas significant effects on adipogenesis, i.e., surperimposed lipid accumulation and gene transcriptional regulations were measured after 3 to 4 d. Combination of selected times for analysis of lipid contents, cell counts, size fractionations, and gene transcriptional regulations showed that FAT/CD36 specific inhibitor AP5258 significantly increased cell survival of oleic acid-treated mouse and human adipocytes, and partially restored the transcriptional response to oleic acid in the presence of insulin through JNK pathway. Taken together, these data open new perspectives to study the molecular mechanisms commonly dysregulated in mouse and human obesity at the level of lipogenesis linked to hypertrophy and adipogenesis linked to hyperplasia

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Gene network analysis leads to functional validation of pathways linked to cancer cell growth and survival

Cited by 14 publications

References 52 publications

Oleic Acid Uptake Reveals the Rescued Enterocyte Phenotype of Colon Cancer Caco-2 by HT29-MTX Cells in Co-Culture Mode

Oleic Acid Uptake Reveals the Rescued Enterocyte Phenotype of Colon Cancer Caco-2 by HT29-MTX Cells in Co-Culture Mode

MicroRNA expressions associated with progression of prostate cancer cells to antiandrogen therapy resistance

Pathways commonly dysregulated in mouse and human obese adipose tissue: FAT/CD36 modulates differentiation and lipogenesis

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