Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA139263 | ENA |
REPOSITORIES: ENA
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Project description:The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early-stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery. In these studies, we systematically profiled gene expression in normal (NHBE), immortalized (BEAS-2B) and fully transformed (NNK-BEAS-2B) human bronchial epithelial cells, as well as a non-small cell lung cancer (NSCLC) cell line (H157) from a smoker. Expression profiles that accompany the immortalization and/or transformation of bronchial epithelial cells were generated, and expression of 28 genes was validated by immunoblotting. 4 of them were further evaluated in immunohistochemical analyses of tissue microarrays that contain NSCLC specimens, surrounding non-diseased tissues and non-pulmonary normal tissues. Although all 4 genes were predominantly expressed in tumor tissues, loss of expression of cytoplasmic CDK1 was clinically important because it was associated with a poor prognosis for NSCLC patients. This poor prognostic value may be associated with therapeutic resistance because decreasing levels of cytoplasmic CDK1 in vitro increased resistance to standard chemotherapies used in the treatment of NSCLC, especially microtubule agents where resistance was almost complete. These studies illustrate how a combined microarray approach can facilitate the identification of new, relevant targets in cancer.
2011-03-31 | GSE28282 | GEO
Project description:The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early-stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery. In these studies, we systematically profiled gene expression in normal (NHBE), immortalized (BEAS-2B) and fully transformed (NNK-BEAS-2B) human bronchial epithelial cells, as well as a non-small cell lung cancer (NSCLC) cell line (H157) from a smoker. Expression profiles that accompany the immortalization and/or transformation of bronchial epithelial cells were generated, and expression of 28 genes was validated by immunoblotting. 4 of them were further evaluated in immunohistochemical analyses of tissue microarrays that contain NSCLC specimens, surrounding non-diseased tissues and non-pulmonary normal tissues. Although all 4 genes were predominantly expressed in tumor tissues, loss of expression of cytoplasmic CDK1 was clinically important because it was associated with a poor prognosis for NSCLC patients. This poor prognostic value may be associated with therapeutic resistance because decreasing levels of cytoplasmic CDK1 in vitro increased resistance to standard chemotherapies used in the treatment of NSCLC, especially microtubule agents where resistance was almost complete. These studies illustrate how a combined microarray approach can facilitate the identification of new, relevant targets in cancer. Fluorescently labeled cDNA were synthesized from 100 microgram RNA by oligo(dT)-primed reverse transcription in the presence of Cy3- or Cy5-dUTP (Amersham Bisciences, Piscataway, NJ). Purified Cy3/Cy5-labelled probes were combined and hybridized in the presence of 2x Denhart's solution, 3.2x saline sodium citrate (SSC), and 0.5% sodium dodecyl sulfate (SDS) in a humidified chamber at 65°C overnight. Prior to scanning (Agilent Technologies, Foster City, CA), slides were successively washed at 22°C in 0.5x SSC/0.1% SDS for 2 min, 0.5x SSC/0.01% SDS for 2 min, and 0.06x SSC for 2 min. Image analyses were performed with the IPLab software (Fairfax, VA). The reference cell (NHBE) was included in every individual hybridization to allow for normalization of each clone’s expression relative to the reference for each cell line (BEAS-2B, NNK-BEAS-2B or H157). A self-to-self hybridization with dye reversal was performed to exclude preferential differences in probe labeling (not included here). Every sample was labeled with Cy5 and Cy3 and hybridized twice. The two fluorescent images (red and green channels) obtained from the scanner constituted the intensity raw data from which differential gene expression ratios and quality control values were calculated. All data were entered into a relational database, using the FileMaker Pro 5 software (Santa Clara, CA). Genes were identified as differentially regulated only if corrected red/green hybridization signals differed by at least two-fold. The genes in each group were alphabetically listed and the ratios of BEAS-2B/NHBE, NNK-BEAS-2B/NHBE or H157/NHBE were graphically visualized by Cluster and TreeView programs (http://rana.lbl.gov/EisenSoftware.htm). These methods fulfilled the MIAME criteria (http://www.mged.org/miame).
2011-03-31 | E-GEOD-28282 | biostudies-arrayexpress
Project description:Approximately 40% ERα-positive breast cancer patients suffer from therapeutic resistance to tamoxifen. Although reduced ERα level is the major cause of tamoxifen resistance, the underlying mechanisms remain elusive. Here, we report that FRMD8 raises the level of ERα at both transcriptional and post-translational layers. FRMD8 deficiency in MMTV-Cre+; Frmd8fl/fl; PyMT mice accelerates mammary tumor growth and loss of luminal phenotype, and confers tamoxifen resistance. Single-cell RNA profiling reveals that Frmd8 loss decreases the proportion of hormone-sensing differentiated epithelial cells and downregulates the levels of ERα. Mechanically, on one hand, loss of FRMD8 inhibits ESR1 transcription via suppressing the expression of FOXO3A, a transcription factor of ESR1. On the other hand, FRMD8 interacts both with ERα and UBE3A, and disrupts the interaction of UBE3A with ERα, thereby blocking UBE3A-mediated ERα degradation. In breast cancer patients, FRMD8 gene promoter is found hypermethylated and low level of FRMD8 predicts poor prognosis. Therefore, FRMD8 is an important regulator of ERα and may control therapeutic sensitivity to tamoxifen in ERα-positive breast cancer patients.
2025-04-09 | GSE244582 | GEO
Project description:Aneuploidy, a cancer hallmark, drives chromosomal instability, drug resistance, and clinically-aggressive tumors. Cyclin-dependent kinase 2 (CDK2) antagonism with independent inhibitors or CDK2 knock-down triggered anaphase catastrophe. This disrupts supernumerary centrosome clustering, causing multipolar division and apoptosis. Time-lapse fluorescent microscopy of FUCCI cell cycle probes transduced into aneuploid lung cancer cells revealed distinct fates of bipolar and polyploid cells after CDK2 inhibition. Apoptosis occurred in multipolar progeny but was repressed in persistent polyploid cancer cells. RNA-seq analyses after CDK2 inhibition of 4N versus 2N lung cancer cells were enriched for CDK1 pathway and KIF family members. The Cancer Genome Atlas (TCGA) analysis of lung cancers indicated CDK1 and KIF family member overexpression was associated with an unfavorable survival. Intravital microscopy of transplanted lung cancer cells in mice extended findings from the in vitro to in vivo settings. CDK2 inhibition of tumor-bearing mice produced polyploid cancer cells in vivo. These cancer cells were resistant to apoptosis and proliferated despite CDK2 inhibition. In contrast, polyploid populations were rarely detected in CDK2 inhibited human alveolar epithelial cells. These findings are translationally relevant. Combined targeting of CDK2 with CDK1 or kinesin family member antagonists should eliminate polyploid cancer cells, promote apoptosis and augment antineoplastic effects.
2025-04-06 | GSE292967 | GEO
Project description:Chemoresistance in cancer is linked to a subset of cancer cells termed “cancer stem cells” (CSCs), and in particular, those expressing the CD44 variant appear to represent a more aggressive disease phenotype. Herein, we demonstrate that CD44v6 represents a CSC population with increased resistance to chemotherapeutic agents, and its high expression is frequently associated with poor overall survival (OS) (HR:3.04; CI:1.35–6.85; p<0.001) and disease-free survival (DFS) (HR:5.30, CI:1.64–17.12, p<0.01) in CRC patients. CD44v6+ cells showed elevated resistance to chemotherapeutic drugs and significantly high tumor initiation capacity. The inhibition of CD44v6 resulted in the attenuation of self-renewal capacity and re-sensitization to chemotherapeutic agents. Of note, miRNA profiling of CD44v6+ SDCSCs identified a unique panel of miRNAs indicative of high self-renewal capacity. In particular, miR-1246 was overexpressed in CD44v6+ cells, and associated with poor OS (HR:2.44, CI:1.15–5.18, p<0.05) and DFS (HR:2.37, CI:1.03–5.44, p<0.05) in CRC patients. We demonstrate that CD44v6+ CSCs induced chemoresistance and enhance tumorigenicity in CRC cells, which is in part orchestrated by dysregulated profiles of a distinct panel of miRNAs. These findings provide a rationale for the therapeutic targeting of specific miRNAs, as well as serving as promising prognostic biomarkers in patients with colorectal neoplasia.
2019-02-22 | GSE125904 | GEO
Project description:Transcription profiling of human lung cancer cell A549 lines treated with the chemotherapeutic drug motexafin gaolinium at 4, 12 and 24h timepoints
2025-01-24 | E-GEOD-2189 | ExpressionAtlas
Project description:ErbB2 Pathway Activation upon Smad4 Loss Promotes Lung Tumor Growth and Metastasis [expression]
2015-08-04 | E-GEOD-57133 | ExpressionAtlas
Project description:Oncogene-induced DNA methylation-mediated transcriptional silencing of tumor suppressors frequently occurs in cancer, but the mechanism and functional role of this silencing in oncogenesis is not fully understood. Here, we show that oncogenic epidermal growth factor receptor (EGFR) induces silencing of multiple unrelated tumor suppressors in lung adenocarcinomas and glioblastomas by inhibiting DNA demethylase TET oncogene family member 1 (TET1) via the C/EBPα transcription factor. After oncogenic EGFR inhibition, TET1 binds to tumor suppressor promoters and induces their re-expression via active DNA demethylation. Ectopic expression of TET1 potently inhibits lung and glioblastoma tumor growth, and TET1 knockdown confers resistance to EGFR inhibitors in lung cancer cells. Lung cancer samples exhibited reduced TET1 expression or TET1 cytoplasmic localization in a majority of cases. Collectively, these results identify a conserved pathway of oncogenic EGFR-induced DNA methylation-mediated transcriptional silencing of tumor suppressors, which may have therapeutic benefit for oncogenic EGFR-mediated lung cancers and glioblastomas. HCC827-Del (EGFR L747-S752) and HCC827-Del-TM (EGFR L747-S752/T790M) cell lines were treated with Decitibine (2.5 μM) and Vorinostat (1μM) or as a control cells that were treated with DMSO for 72 hrs. Expression profiling was performed using 3 biological replicates for each condition for a total of 12 samples analyzed.
2016-06-23 | E-GEOD-39292 | biostudies-arrayexpress
Project description:We conducted a transcriptome-wide survey to identify novel hepatocellular carcinoma (HCC)-associated genes that have undergone aberrant alternative splicing. We revealed that the vesicle transport factor (USO1) is a major alternatively spliced target in HCC, mainly composed of a long wild-type isoform (USO1-L) and a short truncated isoform lacking exons 5 and 15 (USO1-S). A markedly increased isoform switching from USO1-L to USO1-S occurs in approximately 80% of HCCs and predicts poor clinical outcomes. USO1-L suppresses HCC cells growth and metastasis through weakening the activation of MAPK/ERK1-ELK1 signaling by interacting with phosphorylated ERK1 and anchoring it onto the Golgi apparatus to reduce its nuclear translocation; while USO1-S confers a loss-of-function effect. The splicing factor SRSF7, which is shown to be hypomethylated and upregulated in HCC, mediates the splicing of USO1-L to produce USO1-S. Notably, the loss of USO1-L in HCC cells induces their resistance to MEK inhibitors; however, restoring USO1-L through antisense oligodeoxynucleotide (ASO)-mediated blockade of switching from USO1-L to USO1-S can reverse this resistance. In summary, our findings highlight the crucial role of aberrantly alternative splicing of USO1 in HCC, as well as the SRSF7-USO1-MAPK axis as a potential target for this malignancy.
2024-04-02 | GSE262667 | GEO
Project description:Expression of TGFβ-inducible myosin-X predicts survival and chemotherapy resistance in squamous cell lung cancer
| PRJNA377341 | ENA