Targeting 14-3-3ζ overcomes resistance to EGFR-TKIs in lung adenocarcinoma via BMP2/Smad/ID1 signaling
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ABSTRACT:
PROVIDER: PRJNA657881 | ENA |
REPOSITORIES: ENA
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Project description:14-3-3ζ has been found to promote the proliferation, metastasis and chemoresistance of cancer cells in several cancers including lung adenocarcinoma; however, its significance in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance remains unknown. Our work uncovers a hitherto unappreciated role of 14-3-3ζ in EGFR-TKI resistance. We determined global gene expression profiling in EGFR-TKI-resistant H1975 cells using microarray analysis.
2020-09-30 | GSE156435 | GEO
Project description:The BMP2/SMAD pathway is a key regulator of TP53-altered erytholeukemia
| PRJNA749766 | ENA
Project description:Background: The 14-3-3ζ protein, which acts as a putative oncoprotein, has been found to promote the proliferation, metastasis, and chemoresistance of cancer cells in several cancers including lung adenocarcinoma (LUAD); however, its significance in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance remains unknown. Methods: The Cancer Genome Atlas (TCGA) database was used to determine 14-3-3ζ expression in pancancer and LUAD. 14-3-3ζ and ID1 expression was then examined in clinical LUAD samples by immunohistochemistry (IHC). Lentiviral transfection with 14-3-3ζ-specific small hairpin RNA (shRNA) was used to establish stable 14-3-3ζ knockdown gefitinib-resistant PC9 (PC9/GR) and H1975 cell lines. The effect of 14-3-3ζ knockdown on reversing EGFR-TKI resistance was determined in vitro by Cell Counting Kit-8 (CCK-8), wound healing, Transwell assays, and flow cytometry. A xenograft tumor model was established to evaluate the role of 14-3-3ζ in EGFR-TKI resistance. Microarray analysis results showed multiple pathways regulated by 14-3-3ζ-shRNA. Results: In the present study, we demonstrated that based on the TCGA, pancancer and LUAD 14-3-3ζ expression was elevated and predicted unfavorable prognosis. In addition, high 14-3-3ζ expression was associated with advanced T stage, TNM stage, presence of lymph node metastasis and, importantly, poor treatment response to EGFR-TKIs in LUAD patients with EGFR-activating mutations. 14-3-3ζ shRNA sensitized EGFR-TKI-resistant human LUAD cells to gefitinib and reversed epithelial-to-mesenchymal transition (EMT). After 14-3-3ζ depletion, bone morphogenetic protein (BMP) signaling activation was decreased in EGFR-TKI-resistant cells in microarray analysis, which was further validated by Western blot analysis. Furthermore, the expression of 14-3-3ζ positively correlates with ID1 expression in human EGFR-mutant LUAD patient samples. In vivo, there was a reduction in the tumor burden in mice treated with 14-3-3ζ shRNA and gefitinib compared to mice treated with gefitinib alone. Conclusion: Our work uncovers a hitherto unappreciated role of 14-3-3ζ in EGFR-TKI resistance. This study might provide a potential therapeutic approach for treating LUAD patients harboring EGFR mutations.
| S-EPMC7571474 | biostudies-literature
Project description:Epigenetically silenced Ink4a-Arf locus is activated by loss of H3K27me3 in cellular senescence, where secreted factor expression is also involved. Here we analyzed epigenome and transcriptome alteration during Ras-induced senescence using mouse embryonic fibroblast (MEF). Seventeen genes with H3K27me3 loss and H3K4me3 gain showed marked upregulation, including p16Ink4a and Bmp2, a secreted factor for BMP/SMAD signal. Smad6, specific BMP/SMAD pathway inhibitor, was identified as the only one gene showing de novo H3K27 trimethylation with H3K4me3, resulting in strong repression. Ras-activated cells senesced with SMAD1/5/8 phosphorylation, and they escaped from senescence with decreased SMAD1/5/8 phosphorylation when introducing Smad6 or knocking-down Bmp2.
2011-12-22 | GSE18125 | GEO
Project description:The BMP2/SMAD pathway is a key regulator of TP53-altered erytholeukemia [scRNA-seq]
| PRJNA749461 | ENA
Project description:To explore the molecular basis by which Id1 loss promotes HSC quiescence under stress we compared the transcriptome of Id1-/- and Id1+/+ HSCs isolated from primary BMT recipient mice by RNA-seq. We found 179 upregulated and 1476 downregulated genes in Id1-/- HSCs compared to Id1+/+ HSCs using a fold-change cut-off of 2 . Collectively, the IPA analysis shows that Id1-/- HSCs have gene expression profiles consistent with reduced response to stress, reduced cycling and proliferation, and reduced ribosomal biogenesis and protein synthesis, which is consistent with our hypothesis that Id1-/- HSCs have molecular signature of quiescent HSCs compared to Id1+/+ HSCs.
2018-08-09 | GSE114533 | GEO
Project description:The BMP2/SMAD pathway is a key regulator of TP53-altered erytholeukemia [Bulk RNA-seq]
| PRJNA749774 | ENA
Project description:The transforming growth factor beta (TGF-β) superfamily proteins are potent regulators of cellular development and differentiation. Long non-coding RNAs (lncRNAs) play widespread roles in spatial-temporal regulation of early development. However, the roles of lncRNAs regulated by nodal/TGF-β signaling is still elusive. Here, we showed a nodal-driven Smad induced lncRNA in mouse embryonic stem cells (mESCs), lncRNA-Smad7, which is divergently transcribed to Smad7, regulates cell fate determination through repressing Bmp2. Depletion of lncRNA-Smad7 dramatically impairs cardiomyocyte differentiation in mESCs. Moreover, LncRNA-Smad7 represses Bmp2 expression and binds at the promoter region of Bmp2. Importantly, knock-down Bmp2 rescues the defect of cardiomyocyte differentiation. Hence, we showed that lncRNA-Smad7 is antagonistic to BMP signaling in mESCs. Furthermore, lncRNA-Smad7 regulates cell fate determination between osteocytes and myocytes formation in C2C12 cells by repressing Bmp2. Thus, we provide new insights regarding the antagonistic effects between nodal/TGF-β and BMP signaling via lncRNA-Smad7.
2022-10-19 | GSE178136 | GEO
Project description:Trascriptional profiling by array of bone marrow derived murine cells trasduced with control and Id1-overexpressing vectors to identify genes changes induced by increased expression of the transcriptional regulator Id1
2015-03-31 | E-MTAB-2280 | biostudies-arrayexpress
Project description:Acute Myeloid Leukemia (AML) which occurs after an antecedent myeloproliferative neoplasm (MPN) has a dismal clinical prognosis and is not curative outside of the rare subset of patients who undergo successful allogeneic stem cell transplantation. As such, there is a pressing need for new mechanistic insights into how MPNs transform into AML and to use these insights to credential novel therapeutic approaches. The most common somatic mutational event which occurs in transformation from MPN to AML is mutation in TP53. However, the impact of TP53 allelic state on the ability to potentiate leukemic transformation, as well as the pathways involved in this process, have largely remained unresolved. Here we report the development of genetically accurate models of Jak2/Tp53 mutant MPN which undergoes progressive leukemic transformation with chromosomal instability similar to that observed in the clinical context. These models result in a fulminant erythroleukemia phenotype. We identify that leukemic transformation requires homozygous inactivation of TP53, and does not occur with heterozygous loss of Tp53. We further identify that the megakaryocyte erythroid progenitor (MEP) population is expanded prior to and after leukemic transformation, is characterized by progressive genomic instability (compared to other stem/progenitor compartments), and is capable of propagating the disease in vivo. Thus, the leukemia-initiating population is contained in the MEP compartment. Using gene-expression profiling we demonstrate that the BMP2/SMAD pathway (which is involved in self-renewal and DNA damage repair) is aberrantly activated in the leukemic phase of the disease. Importantly, attenuation of Bmp2 results in decreased self-renewal of leukemic cells in vitro and increased survival of leukemic mice in vivo, thus credentialing a biologic role for this pathway in leukemic transformation. Finally, given the loss of Tp53 function and associated disruption of DNA repair pathways, we hypothesized and subsequently identified that leukemic transformation is characterized by increased DNA damage. Using a synthetic-lethality strategy of targeting remaining DNA-repair pathways, using small-molecule inhibitors, in order to provoke biologically intolerable DNA damage and mitotic catastrophe, we demonstrate that Jak2/Tp53 mutant is highly sensitive to combined inhibition of WEE1 and PARP. This combination results in prolonged survival of mice and attenuates the leukemic phenotype. Collectively, these observations yield new mechanistic insights into the process of leukemic transformation resulting from TP53 alterations, and offer new, clinically-translatable, therapeutic options.
2022-05-24 | GSE180772 | GEO