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Regulation of HB-EGF by miR-212 and acquired cetuximab-resistance in head and neck cancer

ABSTRACT: To determine the mechanism of cetuximab-resistance in head and neck cancer, a cetuximab-sensitive cell line (SCC1) and its cetuximab-resistant derivative (1Cc8) were analyzed for differentially expressed genes using DNA microarrays. 900 differentially expressed genes were found using the statistical cut-off point of one-way ANOVA with FDR less than 1%. The SCC1 and 1Cc8 cell lines were grown in biological triplicates. Total RNA was isolated and array experiments were performed. The supplementary file 'GSE21483_differentially_expressed_genes.txt' includes the list of differentially expressed genes that were identified.

ORGANISM(S): Homo sapiens

SUBMITTER: Christine Chung

PROVIDER: E-GEOD-21483 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma.

Hatakeyama Hiromitsu H Cheng Haixia H Wirth Pamela P Counsell Ashley A Marcrom Samuel R SR Wood Carey Burton CB Pohlmann Paula R PR Gilbert Jill J Murphy Barbara B Yarbrough Wendell G WG Wheeler Deric L DL Harari Paul M PM Guo Yan Y Shyr Yu Y Slebos Robbert J RJ Chung Christine H CH

PloS one 20100913 9

<h4>Background</h4>We hypothesized that chronic inhibition of epidermal growth factor receptor (EGFR) by cetuximab, a monoclonal anti-EGFR antibody, induces up-regulation of its ligands resulting in resistance and that microRNAs (miRs) play an important role in the ligand regulation in head and neck squamous cell carcinoma (HNSCC).<h4>Methodology/principal findings</h4>Genome-wide changes in gene and miR expression were determined in cetuximab-sensitive cell line, SCC1, and its resistant derivat ...[more]

PMID: 20856931

Similar Datasets

Regulation of HB-EGF by miR-212 and acquired cetuximab-resistance in head and neck cancer

Project description:To determine the mechanism of cetuximab-resistance in head and neck cancer, a cetuximab-sensitive cell line (SCC1) and its cetuximab-resistant derivative (1Cc8) were analyzed for differentially expressed genes using DNA microarrays. 900 differentially expressed genes were found using the statistical cut-off point of one-way ANOVA with FDR less than 1%.

2011-01-14 | GSE21483 | GEO

Overcoming cetuximab resistance in HNSCC: The role of AURKB and DUSP proteins

Project description:Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Out microarray results suggest that resistant cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP 5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC 4 head and neck squamous cell carcinoma (HNSCC) cell lines were treated with either 15 nM cetuximab or PBS during 13 hours. For each cell line, differential gene expression was assessed between cetuximab and PBS treatments.

2014-09-18 | E-GEOD-61495 | biostudies-arrayexpress

Cetuximab resistant or sensitive head and neck cancer samples

Project description:10 cell lines (five cetuximab sensitive and five cetuximab resistant) were selected for gene copy number array analysis on the Affymetrix SNP 6.0 platform. 39 protein coding genes were amplified in cetuximab resistant cells and normal in sensitive cells, all present on genomic regions 11q22.1 or 5p13-15. Five genes were selected for quantitative PCR verification, namely, YAP1 and TRPC6 (11q22.1) and PDCD6, TPPP, and PTGER4 (5p13-15). An extended panel of totally 10 cetuximab resistant and 10 sensitive cell lines verified that YAP1 amplified cells are cetuximab resistant. YAP1 gene amplification was highly correlated to the YAP1 mRNA expression, which was significantly higher in cetuximab resistant cells than in sensitive. YAP1 downregulation resulted in increased cetuximab sensitivity in one of two cetuximab resistant cell lines investigated and growth inhibition in another. We conclude that YAP1 is a marker for cetuximab resistance in head and neck cancer. head and neck cancer cell lines with established cetuximab response were selected. 5 cetuximab resistant cell lines and 5 cetuximab sensitive cell lines were selected for gene genome wide gene copy number analysis on the Affymetrix SNP6.0 array

2012-12-01 | E-GEOD-36790 | biostudies-arrayexpress

Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients

Project description:Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4–RET and LMNA–NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.

2019-09-21 | E-MTAB-8340 | biostudies-arrayexpress

Identification and functional characterization of proteins interacting with cohesin complex in yeast Saccharomyces cerevisiae.

Project description:To ensure equal separation of DNA, sister chromatids are held together from S phase to metaphase–anaphase transition by a multiprotein complex called cohesin. This makes it possible to establish chromosome biorientation, counteracts the pulling force of mitotic spindle microtubules, preventing premature sister chromatid separation, and ensures precise segregation of sister DNAs into daughter cells In order to better understand how the sister chromatid cohesion process is regulated we looked for new cohesin interacors. We constructed a yeast strain endogenously expressing TAP-tagged Scc1 (Scc1-TAP). Next, we performed a single-step TAP purification using an untagged strain (mock sample) or a strain expressing Scc1-TAP, followed by identification of co-purifying proteins by MS.

2023-10-24 | PXD037034 | Pride

Gene expression signatures modulated by epidermal growth factor receptor activation and their relationship to cetuximab resistance in head and neck squamous cell carcinoma

Project description:Aberrant activation of signaling pathways controlled in normal epithelial cells by the epidermal growth factor receptor (EGFR) has been linked to cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to either ligand stimulation or pharmacological inhibition of the signaling intermediaries PI-3-Kinase and MEK or transfected with EGFR, RELA/p65, or HRASVal12. The gene expression patterns that distinguished the various HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS). This approach inferred gene expression signatures with greater relevance to cell signaling pathway activation than the expression signatures inferred with standard linear models. Furthermore, the pathway signature generated using HaCaT-HRASVal12 further associated with the cetuximab treatment response in isogenic cetuximab-sensitive (UMSCC1) and -resistant (1CC8) cell lines. Our data suggest that the CoGAPS algorithm can generate gene expression signatures that are pertinent to downstream effects of receptor signaling pathway activation and potentially be useful in modeling resistance mechanisms to targeted therapies. 58 total RNA collected from HaCaT cell lines with combinations of the following experimental conditions: forced expression of EGFR, RELA/p65, and HRAS-VAL12D; grown in PBS, serum starve, and media stimulated with TNF or EGF; treated with gefitinib, LY294002, and U1026.

2012-05-22 | E-GEOD-32975 | biostudies-arrayexpress

RING1B calibrated ChIP-seq (cChIPseq) datasets for control mESCs and an Scc1-AID auxin-inducible degron.

Project description:We examined 3D chromatin structure in the absence of cohesin (Scc1-AID auxin-inducible degron) and a control line (E14-Tir1) and found that PRC1 core promoter component RING1B was one of the most enriched proteins. Hence, we performed calibrated ChIP-seq experiments on the control (E14-Tir1) and the Scc1-AID mESC lines with a spike in of HEK293 human cells to further study this relationship.

2020-01-23 | E-MTAB-7817 | biostudies-arrayexpress

Understanding molecular mechanisms of Cetuximab insensitivity in Colorectal Cancer (CRC)

Project description:Mutational status of KRAS in CRC is used to aid patient stratification for Cetuximab treatment. However, only a subset (10-40%) of patients with wt KRAS respond. We analyzed 40 mCRC tumors for Cetuximab response using a functional ex vivo platform. In the subset of non-responsive tumors, mutational (KRAS/BRAF and PIK3CA) and expression (AREG/EREG) analysis of key genes, transcriptomic profiling and GSEA were carried out to elucidate the molecular mechanisms underlying the response. Our analysis revealed deregulation of multiple pathways, notably Notch and Erbb2 and combined blockade of these two nodes elicited significant antitumor response. These findings collectively indicate the dependence of Cetuximab insensitive mCRC tumors on Notch and Erbb2 for survival and progression. 8 Primary tumors tested in ex vivo platform for response to Cetuximab were subjected to expression analysis

2014-04-01 | E-GEOD-56386 | biostudies-arrayexpress

DNA double-strand breaks and 3D chromatin conformation (Hi-C, 4C-seq, ChIP-seq)

Project description:DNA Double-Strand Breaks (DSBs) are highly detrimental since they can lead to mutations and chromosomes rearrangements (amplification, deletion, translocation and chromosome loss). Here, we set to assess the tridimensional genome organization around DSBs and its role in DSB repair foci formation. We performed Hi-C experiments before and after DSB induction and upon ctrl or SCC1 depletion, 4C-seq experiments before and after DSB induction and upon cohesin (SCC1) depletion or ATM inhibition. We also performed ChIP-seq of pATM(S1981), CTCF, P-SMC3(S1083), MDC1 and a calibrated ChIP-seq of SCC1 with or without damage. ChIP-chip of SMC3 (S1083) and SMC1 (S966) were used to show the recruitment of these marks on DNA repair foci. ChIP-chip of gammaH2AX was realized upon SCC1 depletion and ChIP-seq of gammaH2AX was realized upon SCC1 or WAPL to show the role of the cohesin complex in gammaH2AX foci formation. ChIP-seq of gammaH2AX was realized upon ATM or ATR inhibition to show that ATM is the major kinase that phosphorylates H2AX at clean breaks in human cells.

2021-01-29 | E-MTAB-8851 | biostudies-arrayexpress

Capture-C experiments on auxin treated control (E14-Tir) and Scc1-AID, Ring1b-AID, Ring1b-AID-Scc1-AID and CTCF-AID (with and without a 6-hour auxin treatment) cells

Project description:The aim of the experiment was to gain a higher resolution for specific regions of interest to complement the Hi-C results. Capture-C experiments were performed on four-inducible degrons for Scc1, Ringb, Ring1b-Scc1 and CTCF, and Tir1 control, always in triplicates (three biological replicates per condition).

2020-01-23 | E-MTAB-7840 | biostudies-arrayexpress

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