Encapsulated miR-200c and Nkx2.1 in a nuclear/mitochondria transcriptional regulatory network of non-metastatic and metastatic lung cancer cells
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ABSTRACT:
PROVIDER: PRJNA514806 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8436160.fastq.gz | Fastqsanger.gz | |||
| SRR8436151.fastq.gz | Fastqsanger.gz | |||
| SRR8436161.fastq.gz | Fastqsanger.gz | |||
| SRR8436152.fastq.gz | Fastqsanger.gz | |||
| SRR8436162.fastq.gz | Fastqsanger.gz |
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Project description:Background: MicroRNAs are noncoding RNA molecules of ~22 nucleotides with diagnostic and therapeutic action, affecting the expression of mRNAs involved in invasion, migration, and development. miR-200c is part of the miR-200c/141 cluster on chromosome 12p13. Its mechanism of action when encapsulated is critical in lung cancer when patients express changes in miRNAs. miR-200c be a potential biomarkers for various lung diseases. As a potential therapy, miR-200c can impact lives as target lung cancer is a leading cause of death with about 234,000 cases annually, high heterogeneity, complex screening, and a 5-year survival rate of 16%. Encapsulated miR-200c efficiently enhances bioavailability, pharmacokinetics of therapeutics and targeting to cells, improves efficacy and provides potential cure. Methods: The functions of miR-200c were determined in non-metastatic KW-634 and metastatic 821-T4 and 821-LN mouse lung cancer cell lines after various nano vehicle treatments. Viability and cytotoxicity were determined by cell cycle and quantitative real-time PCR analyses were used to quantify levels of miR-200c and its target genes. In situ hybridization was used to visualize patterns of expression of miR-200c and others in the lung and many organs. Next-generation sequencing, invasion and migration assays using transwell chambers, and ActivSignal were used to elucidate the activation and inhibition profiles and perform direct expression measurements and modification of cellular components.
2019-01-12 | GSE125000 | GEO
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Project description:A subset of long-noncoding RNAs (lncRNAs) are spatially correlated with transcription factors (TFs) across the genome, but how these lncRNA-TF gene duplexes regulate tissue development and homeostasis is unclear. We have identified a feedback loop within the NANCI-Nkx2.1 gene duplex that is essential for buffering Nkx2.1 expression, lung epithelial cell identity, and tissue homeostasis. Within this locus, Nkx2.1 directly inhibits NANCI, while NANCI acts in cis to promote Nkx2.1 transcription. Although loss of NANCI alone does not adversely affect lung development, concurrent heterozygous mutations in both NANCI and Nkx2.1 leads to persistent Nkx2.1 deficiency and reprogramming of lung epithelial cells to a posterior endoderm fate. This disruption in the NANCI-Nkx2.1 gene duplex results in a defective perinatal innate immune response, tissue damage, and progressive degeneration of the adult lung. These data point to a mechanism where lncRNAs act as rheostats within lncRNA-TF gene duplex loci that buffer TF expression, thereby maintaining tissue specific cellular identity during development and postnatal homeostasis.
2017-09-08 | GSE92304 | GEO
Project description:Claudin-low tumors are a highly aggressive breast cancer subtype with no targeted treatments and a clinically documented resistance to chemotherapy. They are significantly enriched in cancer stem cells (CSCs), which makes claudin-low tumor models particularly attractive for studying CSC behavior and developing novel approaches to minimize CSC therapy resistance. One proposed mechanism by which CSCs arise is via an epithelial-mesenchymal transition (EMT), and reversal of this process may provide a potential therapeutic approach for increasing tumor chemosensitivity. Therefore, we investigated the role of the miR-200 family of microRNAs in regulating the epithelial state, stem-like properties, and therapeutic response in an in vivo primary, syngeneic p53null claudin-low tumor model that is normally deficient in miR-200 expression. Using an inducible lentiviral approach, we expressed the miR-200c cluster in this claudin-low model and found that it changed the epithelial state, and consequently, impeded CSC behavior in these mesenchymal tumors. Moreover, these state changes were accompanied by a decrease in proliferation and an increase in the differentiation status. MiR-200c expression also forced a significant reorganization of tumor architecture, affecting important cellular processes involved in cell-cell contact, cell adhesion, and motility. Accordingly, induced miR200c expression also significantly enhanced the chemosensitivity and decreased the metastatic potential of this p53null claudin-low tumor model. Collectively, our data suggest that miR-200c expression in claudin-low tumors offers a potential therapeutic application to disrupt the EMT program on multiple fronts in this mesenchymal tumor subtype, by altering tumor growth, chemosensitivity, and metastatic potential in vivo. reference x sample
2015-06-22 | E-GEOD-62230 | biostudies-arrayexpress
Project description:Claudin-low tumors are a highly aggressive breast cancer subtype with no targeted treatments and a clinically documented resistance to chemotherapy. They are significantly enriched in cancer stem cells (CSCs), which makes claudin-low tumor models particularly attractive for studying CSC behavior and developing novel approaches to minimize CSC therapy resistance. One proposed mechanism by which CSCs arise is via an epithelial-mesenchymal transition (EMT), and reversal of this process may provide a potential therapeutic approach for increasing tumor chemosensitivity. Therefore, we investigated the role of the miR-200 family of microRNAs in regulating the epithelial state, stem-like properties, and therapeutic response in an in vivo primary, syngeneic p53null claudin-low tumor model that is normally deficient in miR-200 expression. Using an inducible lentiviral approach, we expressed the miR-200c cluster in this claudin-low model and found that it changed the epithelial state, and consequently, impeded CSC behavior in these mesenchymal tumors. Moreover, these state changes were accompanied by a decrease in proliferation and an increase in the differentiation status. MiR-200c expression also forced a significant reorganization of tumor architecture, affecting important cellular processes involved in cell-cell contact, cell adhesion, and motility. Accordingly, induced miR200c expression also significantly enhanced the chemosensitivity and decreased the metastatic potential of this p53null claudin-low tumor model. Collectively, our data suggest that miR-200c expression in claudin-low tumors offers a potential therapeutic application to disrupt the EMT program on multiple fronts in this mesenchymal tumor subtype, by altering tumor growth, chemosensitivity, and metastatic potential in vivo.
2015-06-22 | GSE62230 | GEO
Project description:We performed RNA sequencing of islets of Langerhans isolated from RipmiR-141~200c and RipmiR-141~200c Zeb1200M mice to determine the transcriptomic effects of mutating miR-200 binding sites in the endogenous Zeb1 3'UTR of mice in which miR-141~200c is overexpressed under the rat insulin promoter (RIP).
2022-04-30 | E-MTAB-10537 | biostudies-arrayexpress
Project description:We performed microarray analysis on BT549 cells that express miR-200c in a doxycycline (dox)-inducible manner from the miR-200c-TripZ system.
2017-12-20 | GSE108271 | GEO
Project description:Mitochondrial transplantation has been proposed as a strategy to restore cellular bioenergetics after oxidative injury, but the mechanisms governing ATP recovery remain unclear. Using placental mitochondria, we examined ATP restoration following H₂O₂-induced oxidative stress. Unmodified mitochondria modestly increased ATP under baseline conditions but failed to restore ATP after injury. In contrast, lipid-coated mitochondria (MitoCoat) and lipid-encapsulated mitochondria-associated mRNAs (MitoCoat-mRNA) significantly increased ATP levels in injured cells. Transcriptomic analyses revealed that ATP recovery occurred without normalization of canonical glycolytic or oxidative phosphorylation (OXPHOS) gene programs. Instead, unmodified mitochondria induced broad transcriptional responses associated with immune activation and cellular stress, whereas MitoCoat elicited a more restricted transcriptional profile. Notably, mitochondria-associated mRNAs alone restored ATP without detectable changes in host transcriptional programs. Removal of mitochondrial surface–associated ribosomes or inhibition of cytosolic but not mitochondrial translation attenuated ATP recovery. Restoration of key metabolic enzymes through cytosolic translation, including PFKP, pyruvate dehydrogenase, and ATP synthase subunit ATP5A, suggests that mitochondria-associated mRNAs promote recovery by re-establishing coupling between glycolysis and mitochondrial OXPHOS. Together, these findings identify encapsulated mitochondria-associated mRNAs as a potential strategy to restore cellular bioenergetics under oxidative stress.
2026-06-03 | GSE326220 | GEO
Project description:Nkx2.1 is a critical regulator of mammalian lung development. It is expressed in epithelial cells at the initiation of lung organogenesis, becoming progressively restricted during development to bronchiolar and alveolar type II epithelial cells. In humans, it is a common marker of carcinomas of lung and thyroid origin and is highly amplified in 10-15% of lung adenocarcinomas. Despite its key role in development and disease only a few genes directly regulated by Nkx2.1 are known. To identify direct Nkx2.1target genes and pathways controlled by this transcription factor in vivo we analyzed, by chromatin immuno-precipitation (chip)-on-chip method, Nkx2.1 binding to DNA cis-elements in developing mouse lung. We analyzed embryonic day E11.5 lungs, when Nkx2.1 expressing cells are undergoing predominantly proliferation, and day E19.5, when Nkx2.1 expressing cells are undergoing predominantly differentiation. Many highly bound targets are known and well described, such as surfactant proteins and secretoglobins. Unique or common target genes involved in a variety of developmental and tumorigenic pathways were identified at each developmental time point. Positive regulation of cell proliferation was the highest overrepresented biological process at E11.5 while ion transport was the highest overrepresented biological process at E19.5. New identified targets include proliferation related genes such as E2F3, Met, Ccnb1, and Ccnb2. Nkx2.1 downregulation in mouse epithelial and human carcinoma cell lines reduced cell proliferation by arresting cells in the G2/M phase. Reduced expression of Nkx2.1 target genes in both cell lines supports a direct role of Nkx2.1 in regulation of cell proliferation genes. The identification of these transcriptional regulatory pathways in vivo aid us to understand Nkx2.1 function in lung development and link it to disease, since many of the identified targets are aberrantly up regulated in cancer cells. Developing mouse lung, 2 developmental time points E11.5 and E19.5, genomic DNA fragments immunoprecipitated with a-Nkx2.1 (07-601, Upstate-Millipore) vs input, E11.5, 2 biological replicates and E19.5, 3 biological replicates
2011-11-01 | E-GEOD-23043 | biostudies-arrayexpress
Project description:Macrophages constitute a major part of the tumor-infiltrating immune cells and within the tumor microenvironment acquire an alternatively activated, tumor-supporting phenotype. Factors released by tumor cells are crucial for the recruitment of tumor-associated macrophages. In the present project, we aimed to understand the role of miR-200c in the interplay between tumor cells and macrophages. To this end, we employed a coculture system of MCF7 breast tumor cells and primary human macrophages and observed a substantial transfer of miR-200c from apoptotic tumor cells to macrophages, which required intact CD36 receptor in macrophages. We further comprehensively determined miR-200c targets in macrophages by mRNA-sequencing and found numerous migration-associated mRNAs to be downregulated by miR-200c. Consequently, miR-200c attenuated macrophage infiltration into 3-dimensional tumor spheroids. The miR-200c-mediated reduction of infiltration further correlated well with a miR-200c migration signature comprised of four miR-200c-repressed targets (PPM1F, RAB11FIB2, RDX, MSN).
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