MiRNA-483-3p overexpression unleashes invasive growth of metastatic colorectal cancer via NDRG1 downregulation and ensuing activation of the ERBB3/AKT axis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA861231 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20403634.fastq.gz | Fastqsanger.gz | |||
| SRR20403635.fastq.gz | Fastqsanger.gz | |||
| SRR20403636.fastq.gz | Fastqsanger.gz | |||
| SRR20403637.fastq.gz | Fastqsanger.gz | |||
| SRR20403638.fastq.gz | Fastqsanger.gz |
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Project description:Colorectal cancer is a prevalent disease that is the third most common cause of cancer-associated death globally. The genetic mechanisms underlying tumor aggressiveness in colorectal cancer require further elucidation. Taking advantage of a large panel of human metastatic colorectal cancer xenografts and matched stem-like cell cultures (m-colospheres), we show here that overexpression of miRNA-483-3p, encoded by a frequently amplified gene locus encompassing IGF2, confers an aggressive phenotype. Following ectopic overexpression of miRNA-483-3p, m-colospheres displayed (i) increased proliferative response to exogenous EGFR family ligands EGF and neuregulin 1; (ii) increased spontaneous and growth factor-induced invasiveness and epithelial-mesenchymal transition (EMT); and (iii) enhanced stem-cell frequency and resistance to differentiation. Transcriptomic analyses and functional validation found that miRNA-483-3p directly targets NDRG1, a known metastasis suppressor responsible for downregulation of the EGFR family. As a result, induced or endogenous miRNA-483-3p overexpression associated with stimulation of the signaling pathway triggered by ERBB3, including AKT and GSK3β, which is responsible for EMT transcription factor activation. Consistently, treatment of miRNA-483-3p-overexpressing m-colospheres with selective ERBB3 antibodies counteracted their proliferative and invasive phenotype. The pro-malignant role of miRNA-483-3p was further corroborated by analysis of human colorectal tumors, where miRNA-483-3p expression levels directly correlated with expression of EMT transcription factors and poor prognosis, and downregulation of miRNA-483-3p, which prevented invasion of tumors formed by m-colosphere transplantation. These results unveil a previously unrecognized link between miRNA-483-3p, NDRG1, and ERBB3-AKT signaling, which can directly support colorectal cancer invasion and is amenable to therapeutic targeting.
2023-03-13 | GSE209535 | GEO
Project description:In colorectal cancer, the mechanisms underlying tumor aggressiveness require further elucidation. Taking advantage of a large panel of human metastatic colorectal cancer xenografts and matched stem-like cell cultures (m-colospheres), here we show that the overexpression of microRNA 483-3p (miRNA-483-3p; also known as MIR-483-3p), encoded by a frequently amplified gene locus, confers an aggressive phenotype. In m-colospheres, endogenous or ectopic miRNA-483-3p overexpression increased proliferative response, invasiveness, stem cell frequency, and resistance to differentiation. Transcriptomic analyses and functional validation found that miRNA-483-3p directly targets NDRG1, known as a metastasis suppressor involved in EGFR family downregulation. Mechanistically, miRNA-483-3p overexpression induced the signaling pathway triggered by ERBB3, including AKT and GSK3β, and led to the activation of transcription factors regulating epithelial-mesenchymal transition (EMT). Consistently, treatment with selective anti-ERBB3 antibodies counteracted the invasive growth of miRNA-483-3p-overexpressing m-colospheres. In human colorectal tumors, miRNA-483-3p expression inversely correlated with NDRG1 and directly correlated with EMT transcription factor expression and poor prognosis. These results unveil a previously unrecognized link between miRNA-483-3p, NDRG1, and ERBB3-AKT signaling that can directly support colorectal cancer invasion and is amenable to therapeutic targeting.
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Project description:HaCaT human keratinocytes were transfected with pre-miR-483-3p or pre-miR-NC. RNA samples were harvested 48h post-transfection and mRNA profiles were determined with pan genomic arrays. Two biological replicates were performed for each comparison. Data were normalized using a dye-swap method.
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Project description:N-myc downstream-regulated gene 1 (*NDRG1*) is induced by cellular stress such as hypoxia and DNA damage, and in humans, germ line mutations cause Charcot-Marie-Tooth disease. However, the roles of NDRG1 in the cell are not fully understood. Previously, NDRG1 was shown to mediate doxorubicin resistance under hypoxia, suggesting a role for NDRG1 in cell survival under these conditions. We found decreased apoptosis in doxorubicin-treated cells expressing NDRG1 shRNAs under normoxia, demonstrating a requirement for NDRG1 in apoptosis in breast epithelial cells under normal oxygen pressure. We further compared expression profiles in human breast epithelial cells ectopically over-expressing NDRG1 with cells expressing NDRG1 shRNAs in order to identify biological pathways where NDRG1 is involved. The results suggest that NDRG1 may have roles connected to vesicle transport. The previously reported roles of NDRG1 in apoptosis, myelin sheet maintenance, enhanced exocytosis in mast cells and in cellular responses to hypoxia, heavy metals, and androgen may all converge by NDRG1 having a role linked to vesicle transport.
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Project description:Mammary organoids harvested from ErbB3 DOX-KO mice, which utilize MMTV-Cre transgene expression in the LE to cause genomic recombination at floxed ErbB3 alleles in ErbB3FL/FL were cultured in the presence or absence of doxycycline to induce ErbB3 loss. The gene expression shift following DOX-induced ErbB3 loss in the 3D organoids was examined by microarray. Gene expression patterns were interrogated in mammary organoids from ErbB3 inducible-knockout mice cultured in the presence of absence of doxycycline. Three biological replicates of the experiment were performed, resulting in a total of 6 samples (3 treatment, 3 control).
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Project description:SKBR3 cells expressing NDRG1 shRNA1 or vector control were harvested by trypsinization and total RNA was extracted. Silencing NDRG1 reduces cell proliferation rates, causing lipid metabolism dysfunction including increased fatty acid incorporation into neutral lipids and lipid droplets. global changes in transcriptome due to NDRG1 silencing were observed
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Project description:N-myc downstream-regulated gene 1 (*NDRG1*) is induced by cellular stress such as hypoxia and DNA damage, and in humans, germ line mutations cause Charcot-Marie-Tooth disease. However, the roles of NDRG1 in the cell are not fully understood. Previously, NDRG1 was shown to mediate doxorubicin resistance under hypoxia, suggesting a role for NDRG1 in cell survival under these conditions. We found decreased apoptosis in doxorubicin-treated cells expressing NDRG1 shRNAs under normoxia, demonstrating a requirement for NDRG1 in apoptosis in breast epithelial cells under normal oxygen pressure. We further compared expression profiles in human breast epithelial cells ectopically over-expressing NDRG1 with cells expressing NDRG1 shRNAs in order to identify biological pathways where NDRG1 is involved. The results suggest that NDRG1 may have roles connected to vesicle transport. The previously reported roles of NDRG1 in apoptosis, myelin sheet maintenance, enhanced exocytosis in mast cells and in cellular responses to hypoxia, heavy metals, and androgen may all converge by NDRG1 having a role linked to vesicle transport. SUM102 and ME16C2 stably transduced with siRNA against NDRG1 compared with empty vector control ZR-75-1 stably transduced with NDRG1 overexpression construct compared with empty vector control Two condition design
2011-11-04 | E-GEOD-33437 | biostudies-arrayexpress
Project description:The four members of the epidermal growth factor receptor (EGFR/ERBB) family form homo- and heterodimers which mediate ligand-specific regulation of many key cellular processes in normal and cancer tissues. While signaling through the EGFR has been extensively studied on the molecular level, signal transduction through ERBB3/ERBB4 heterodimers is less well understood. Here, we generated isogenic mouse Ba/F3 cells that express full-length and functional membrane-integrated ERBB3 and ERBB4 or ERBB4 alone, to serve as a defined cellular model for biological and phosphoproteomics analysis of ERBB3/ERBB4 signaling. ERBB3 co-expression significantly enhanced Ba/F3 cell proliferation upon neuregulin-1 (NRG1) treatment. For comprehensive signaling studies we performed quantitative mass spectrometry (MS) experiments to compare the basal ERBB3/ERBB4 cell phosphoproteome to NRG1 treatment of ERBB3/ERBB4 and ERBB4 cells. We employed a workflow comprising differential isotope labeling with mTRAQ reagents followed by chromatographic peptide separation and final phosphopeptide enrichment prior to MS analysis. Overall, we identified 9686 phosphorylation sites which could be confidently localized to specific residues. Statistical analysis of three replicate experiments revealed 492 phosphorylation sites which were significantly changed in NRG1-treated ERBB3/ERBB4 cells. Bioinformatics data analysis recapitulated regulation of mitogen-activated protein kinase and Akt pathways, but also indicated signaling links to cytoskeletal functions and nuclear biology. Comparative assessment of NRG1-stimulated ERBB4 Ba/F3 cells indicated that ERBB3 did not trigger defined signaling pathways but more broadly enhanced phosphoproteome regulation in cells expressing both receptors. In conclusion, our data provide the first global picture of ERBB3/ERBB4 signaling and provide numerous potential starting points for further mechanistic studies
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