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Activating PIK3CA mutation promotes osteogenesis of bone marrow mesenchymal stem cells in macrodactyly

ABSTRACT: Activating PIK3CA mutation promotes osteogenesis of bone marrow mesenchymal stem cells in macrodactyly

PROVIDER: PRJNA621634 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11458989_1.fastq.gz	Fastqsanger.gz
	SRR11458989_2.fastq.gz	Fastqsanger.gz
	SRR11458990_1.fastq.gz	Fastqsanger.gz
	SRR11458990_2.fastq.gz	Fastqsanger.gz
	SRR11458991_1.fastq.gz	Fastqsanger.gz

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Activating PIK3CA mutation promotes osteogenesis of bone marrow mesenchymal stem cells in macrodactyly

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Activating Mutations in PIK3CA result in Widespread Modulation of the Tyrosine Phosphoproteome

Project description:The human oncogene PIK3CA is frequently mutated in human cancers. The two hotspot mutations in PIK3CA, E545K and H1047R, have been shown to regulate widespread signaling events downstream of AKT. However, the impact of these activating mutations on the tyrosine phosphorylation signaling in the cell has not been studied. Here, we performed a global phosphotyrosine profiling using isogenic knockin cell lines containing these activating mutations. We identified 824 unique phosphopeptides from 308 proteins. We found a surprisingly widespread modulation of tyrosine phosphorylation levels of proteins in the knockin mutant cells, with many of the regulated proteins involved in important biological processes, including those in the cytoskeletal migration pathways and kinase regulated signaling. We observed a widespread modulation of the tyrosine kinome, with 24 of the tyrosine kinases showing either upregulation or downregulation in phosphorylation levels. Many of the regulated phosphosites that we identified were located in the kinase domain or the canonical activating sites, indicating that the kinases were active and hence their downstream signaling pathways. Our study thus shows that the activating mutations in PIK3CA result in widespread tyrosine signaling regulation, in addition to the serine/threonine signaling pathways activated by the canonical PI3K-AKT axis.

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Fgf9 promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells differentiation in adult bone marrow

Project description:In this study, we found that Fgf9 regulates the bone-fat balance by modulating the cell fate determination of BMSCs. Histology and micro-CT analysis demonstrate that Fgf9 S99N mutation (loss-of-function) significantly inhibited the formation of bone marrow adipose tissue (BMAT) in adult mice and alleviated the ovariectomized (OVX) induced bone loss and BMAT accumulation. In vitro cytodifferentiation assays unveiled that the Fgf9 S99N mutation hindered adipogenesis while promoting osteogenesis in BMSCs. Furthermore, recombinant FGF9 stimulation and Fgf9 overexpression in BMSCs demonstrated that Fgf9 significantly promoted adipocyte formation and inhibited osteogenesis in vitro and in vivo. Cytodifferentiation assays at various stages of BMSC differentiation indicated that FGF9 altered the osteogenic and adipogenic potential of BMSCs, particularly during the early stages of differentiation. Transcriptomic and gene expression analyses demonstrated that FGF9 significantly upregulated the expression of adipogenic genes while downregulating osteogenic gene expression at both mRNA and protein levels. KEEG analysis revealed and in vitro differentiation assays with specific inhibitors confirmed that FGF9 modulated bone-fat balance by inhibiting osteogenesis via the MAPK/ERK pathway and promoting adipogenesis by activating the PI3K/AKT and Hippo pathways.

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Spinal tuberculosis infection induces osteopenia by reducing the migration and osteogenesis of bone marrow mesenchymal stem cells

Project description:Objectives: Bone marrow mesenchymal stem cells (BMSC) play an important role in osteogenesis. However, the role of BMSC in osteopenia in spinal tuberculosis (STB) patients is unclear. Methods: Bone mineral density (BMD) of 53 STB patients and 55 controls was measured. The migration and osteogenesis of BMSC were assessed by wound healing assays and alizarin red staining, and osteoclast marker expression was measured. RNA-seq was performed on BMSC and the enriched signaling pathways were verified. Results:BMD of STB patients was significantly decreased and BMSC migration and osteogenesis were significantly reduced. After verification, we found that the B-cell receptor signaling pathway, tuberculosis, osteoclast differentiation, Th17-cell differentiation, Ras signaling pathway and PI3K-Akt signaling pathway were affected.And of these pathways, the B-cell receptor signaling, Th17-cell differentiation, Ras signaling pathway and PI3K-Akt signaling pathway were not previously known to be involved in osteopenia. The MAPK signaling pathway and ECM-receptor interactions were correlated with STB prognosis. Conclusion: STB infection can significantly reduce BMSC migration and osteogenesis, decreasing BMD. This process is regulated by multiple pathways and is associated with STB prognosis. Our study suggests that reduced BMSC migration and osteogenesis play important roles in osteopenia in STB patients, and BMSC may be a therapeutic target.

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Project description:Transcriptome expression of human bone marrow mesenchymal stem cell (hBMSCs) during osteogenesis

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2016-07-03 | E-GEOD-71080 | biostudies-arrayexpress

Transcriptome analysis of mouse tumors driven by PIK3CA mutation variants

Project description:The RTK/RAS/PI3K pathway is a key driver of tumorigenesis across all cancers, with 90% of Glioblastoma (GBM) tumors exhibiting alterations in this pathway. Among the specific genes in this pathway mutations in PI3K’s catalytic subunit, PIK3CA, are found in 11% of GBM tumors. Sequencing of GBM samples has revealed several known hotspot mutations that drive tumorigenesis in several cancers (E545K, H1047R), as well as a series of 63 in frame mutations (as indexed in COSMIC) that remain largely unclassified. To decode which of these PIK3CA variants function as drivers of GBM, we established an in vivo complementation screening platform for GBM. Our mouse GBM model relies on in utero electroporation (IUE) and CRISPR-Cas9 mediated knockout of NF1, p53, and PTEN (termed 3xCR). Because PTEN catalyzes the reverse reaction of PIK3CA, phosphorylation of PIP2 to PIP3, we complemented loss of PTEN with overexpression of E545K or H1047R, two bona fide hot spot driver mutations of PIK3CA. Both these variants accelerated tumor associated death, demonstrating that known PIK3CA drivers can complement PTEN loss in our system.

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Gene expression of human bone marrow mesenchymal stem cell (hBMSCs) during osteogenesis with or without TNF-alpha

Project description:In our previous study, we found that TNF-alpha (100ng/mL) different treatment times have opposing effects on BMSC osteogenesis. To investigate the roles of TNF-alpha in the osteogenic differentiation of hBMSCs, we performed gene microarray to detected the gene expression of hBMSCs with or without TNF-alpha during osteogenesis on days 3 and 4.

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Loss of HDAC-mediated repression and gain of NF-kB activation underlies cytokine induction in ARID1A and PIK3CA mutation-driven ovarian cancer

Project description:ARID1A is frequently mutated in ovarian clear-cell carcinoma (OCCC) and often co-exists with activating mutations of PIK3CA. Although induction of pro-inflammatory cytokines has been observed in this cancer, the mechanism by which the two mutations synergistically activate cytokine genes remains elusive. Here we established an in vitro model of OCCC by introducing ARID1A knock-down and mutant PIK3CA in a normal human ovarian epithelial cell line, which resulted in cell transformation and cytokine gene induction. We demonstrate that loss of ARID1A impairs the recruitment of the Sin3A-HDAC complex, while PIK3CA mutation releases RelA from IkB, leading to cytokine gene activation. We show that an NF-kB inhibitor partly attenuates proliferation of OCCC and improves the efficacy of carboplatin both in cell culture and a mouse model. Our study thus reveals the mechanistic link between ARID1A/PIK3CA mutations and cytokine gene induction in OCCC, and suggests NF-kB inhibition can be a potential therapeutic option.

2016-09-15 | GSE86004 | GEO

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