Regulation of HB-EGF by miR-212 and acquired cetuximab-resistance in head and neck cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE21483 | GEO | 2011/01/14
SECONDARY ACCESSION(S): PRJNA126035
REPOSITORIES: GEO
Similar Datasets
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%. 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.
2011-01-14 | E-GEOD-21483 | biostudies-arrayexpress
Project description: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).Genome-wide changes in gene and miR expression were determined in cetuximab-sensitive cell line, SCC1, and its resistant derivative 1Cc8 using DNA microarrays and RT-PCR. The effects of differentially expressed EGFR ligands and miRs were examined by MTS, colony formation, ELISA, and western blot assays. Heparin-binding EGF-like growth factor (HB-EGF) and its regulator, miR-212, were differentially expressed with statistical significance when SCC1 and 1Cc8 were compared for gene and miR expression. Stimulation with HB-EGF induced cetuximab resistance in sensitive cell lines. Inhibition of HB-EGF and the addition of miR-212 mimic induced cetuximab sensitivity in resistant cell lines. MicroRNA-212 and HB-EGF expression were inversely correlated in an additional 33 HNSCC and keratinocyte cell lines. Six tumors and 46 plasma samples from HNSCC patients were examined for HB-EGF levels. HB-EGF plasma levels were lower in newly diagnosed HNSCC patients when compared to patients with recurrent disease.Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance. The combination of EGFR ligand inhibitors or miR modulators with cetuximab may improve the clinical outcome of cetuximab therapy in HNSCC.
| S-EPMC2938338 | biostudies-literature
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
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.
2012-12-01 | GSE36790 | GEO
Project description:Gene Expression Profiling of HT-29 and Caco-2 colon cancer cell lines untreated compared with EGF, Cetuximab, Gefitinib,EGF plus Cetuximab and EGF plus gefitinib treatments. Keywords: Gene Expression Profiling
2007-09-12 | GSE8967 | GEO
Project description:Cetuximab (Erbitux) is an antibody drug against EGFR and commonly used in late stage HNSCC and metastatic colorectal cancer. The oncogenic mutation of certain genes are known to drive Cetuximab resistance such as K-RAS or b-RAF mutation. The aberrant activation of signaling pathways in the presence of Cetuximab treatment to overcome cellular stress contribute to acquired resistance to Cetuximab as well. To better understand the mechanisms and molecular patterns of Cetuximab resistant cells, the Cetuximab resistant cells are trained for examining the gene expression profile. The gene expression array is used for identify the molecular signature governing the Cetuximab resitance.
2017-03-02 | GSE63916 | GEO
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
Project description:The cetuximab resistant FaDuCR cell lines were established after continuous treatments with a 10 µg/mL final concentration of cetuximab. Those cells could freely proliferate in 10 µg/mL cetuximab containing medium, and were named FaDuCR. We used microarrays to detail the gene expression in FaDuCR and FaDu-parental cells to screen for transcripts correlated with cetuximab resistance.
2019-05-14 | GSE131108 | GEO
Project description:Most head and neck cancer (HNC) patients are resistant to cetuximab, an antibody against the epithelial growth factor receptor. Such therapy resistance is known to be mediated, in part, by stromal cells surrounding the tumor cells; however, the mechanisms underlying such a resistance phenotype remain unclear. To identify the mechanisms underlying cetuximab resistance in an unbiased manner, RNA-sequencing (RNA-seq) of HNC patient-derived xenografts (PDXs) was performed. Comparing the gene expression of HNC-PDXs before and after treatment with cetuximab indicated that the TGF-beta signaling pathway was upregulated in the stromal cells of PDXs that progressed to cetuximab (CetuximabProg-PDX). However, in PDXs that were extremely sensitive to cetuximab, and when tumors shrunk following cetuximab treatment (CetuximabSen-PDX), the TGF-beta pathway was downregulated in the stromal compartment. Histopathological analysis of PDXs showed that in CetuximabProg-PDX, TGF-beta-activation was detected in cancer-associated fibroblasts (CAFs). These TGF-beta-activated CAFs were sufficient to limit cetuximab efficacy in vitro and in vivo. Moreover, blocking the TGF-beta pathway using the SMAD3 inhibitor, SIS3, enhanced cetuximab efficacy and prevented the progression of CetuximabProg-PDX. Altogether, our findings indicate, for the first time, that TGF-beta-activated CAFs play a role in limiting cetuximab efficacy in HNC.
2020-03-23 | GSE143279 | GEO
Project description:The antibody trastuzumab in combination with platin-fluoropyrimidine chemotherapy is the standard of care for patients with HER2-positive recurrent or metastatic gastric cancer. Alternative treatment options and biomarkers for prediction of therapy response are needed since some patients do not respond to trastuzumab therapy or develop acquired resistance. We compared the molecular effects of trastuzumab and other HER-targeting drugs cetuximab and afatinib. We also tested the hypothesis that the treatment-dependent regulation of a gene indicates its importance for response, and therefore it may be used as biomarker for patient stratification. The four gastric cancer cell lines Hs746T, MKN1, MKN7 and NCI-N87 were treated with EGF, cetuximab, trastuzumab or afatinib for 4 or 24 hours. The effect on gene expression was then measured by RNA sequencing and the resulting candidate biomarkers were tested in an available cohort of gastric cancer patients or were functionally analyzed in vitro. Treatment with afatinib resulted in the highest number of regulated genes, followed by cetuximab and trastuzumab. Although trastuzumab had little effects on gene expression, we identified BMF, HAS2 and SHB as candidate biomarkers for trastuzumab response. HAS2 and SHB were confirmed as potential predictive markers for trastuzumab therapy response in clinical specimens. AREG, EREG and HBEGF were identified as candidate biomarkers for afatinib and cetuximab treatment. The functional analysis confirmed HBEGF as resistance factor for cetuximab. By confirming HAS2, SHB and HBEGF as biomarkers for anti-HER therapies, we provide evidence that the regulation of gene expression after treatment can be used for biomarker discovery.
2020-11-02 | GSE141352 | GEO