The Rac nucleotide Exchange Factor (Rac-GEF) P-Rex1 is highly expressed in breast cancer, specifically in the luminal subtype, and is an essential mediator of actin cytoskeleton reorganization and cell migratory responses induced by ErbB and other tyrosine-kinase receptors. Heregulin, a growth factor highly expressed in mammary tumors, causes the activation of P-Rex1 and Rac1 in breast cancer cells via ErbB3, leading to a motile response. Since there is limited information about P-Rex1 downstream effectors, we carried out a microarray analysis to identify genes regulated by P-Rex1 in the context of HRG stimulation. In T-47D breast cancer cells, HRG treatment caused major changes in gene expression, including genes associated with motility, adhesion, invasiveness and metastasis. Silencing P-Rex1 expression from T-47D cells using RNAi altered the induction and repression of a subset of HRG-regulated genes, among them genes associated with extracellular matrix organization, migration, and chemotaxis. HRG induction of MMP10, a gene encoding for metalloproteinase-10, was found to be highly sensitive both to P-Rex1 depletion as well as inhibition of Rac1 function by the GTPase Activating Protein (GAP) 2-chimaerin, suggesting the dependence of the P-Rex1/Rac1 pathway for the induction of genes critical for breast cancer invasiveness. Notably, there is a significant association in the expression of P-Rex1 and MMP10 in human luminal breast cancer, and their co-expression is indicative of poor prognosis.
Characterization of a P-Rex1 gene signature in breast cancer cells.
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View SamplesPKCe, an oncogenic member of the PKC family, is aberrantly overexpressed in epithelial cancers. To date, little is known about functional interactions of PKCe with other genetic alterations and the effectors of this kinase that contribute to its tumorigenic and metastatic phenotype. Here we demonstrate that PKCe cooperates with the loss of the tumor suppressor Pten for the development of prostate cancer in a mouse model. Mechanistic analysis revealed that PKCe overexpression and Pten loss individually and synergically cause a remarkable up-regulation in the production of the chemokine CXCL13. Notably, targeted disruption of CXCL13 or its receptor CXCR5 in prostate cancer cells impaired their migratory and tumorigenic properties. In addition to providing evidence for an autonomous vicious cycle driven by PKCe, our studies identified a compelling rationale for targeting the CXCL13:CXCR5 axis for prostate cancer treatment.
Protein Kinase C Epsilon Cooperates with PTEN Loss for Prostate Tumorigenesis through the CXCL13-CXCR5 Pathway.
Cell line
View SamplesAngiotensin II (Ang II) mediated signaling plays a key role in the development of hypertension associated target organ damages. However, the gene expression changes regulated by Ang II in the early stage of acute cerebral, cardiac, renal, vascular injury remain unclear.
Identification of genes related to the early stage of Angiotensin II-induced acute renal injury by microarray and integrated gene network analysis.
Sex, Specimen part
View SamplesThe clinical application of doxorubicin as a broad-spectrum anti-tumor antibiotic is limited greatly by its cardiotoxicity. Various mechanisms have been studied, but little is known about whether genes or pathways relevant with energy metabolism contributes to doxorubicin-induced cardiomyopathy or not.
No associated publication
Treatment
View SamplesIL28B genotype was shown to be associated with treatment outcome of antiviral thearpy for HCV infection. We tried to clarify the molecular feature that was asocciated with IL2B genotype by comparing Hepatic gene expression of HCV related Hepatocellular carcinoma and non-cancerous tissue with Il28B rs8099917 TT genotype and TG/GG genotype.
Association of interleukin-28B genotype and hepatocellular carcinoma recurrence in patients with chronic hepatitis C.
Specimen part
View SamplesSpinal interneurons are critical modulators of locomotor circuit function. In the dorsal spinal cord, a set of interneurons called GABApre presynaptically inhibits proprioceptive sensory afferent terminals, thus negatively regulating sensory-motor signaling. While deficits in presynaptic inhibition have been inferred in human locomotor diseases, including dystonia, it remains unknown whether GABApre circuit components are altered in these conditions. In this study, we use developmental timing to show that GABApre neurons are a late Ptf1a-expressing subclass and localize to the intermediate spinal cord. Using a microarray screen to identify genes expressed in this intermediate population, we find the kelch-like family member Klhl14, implicated in dystonia through its direct binding with torsion-dystonia related protein Tor1a. Furthermore, in Tor1a mutant mice in which Klhl14 and Tor1a binding is disrupted (Dyt1E), GABApre-sensory afferent synapse formation is impaired. Our findings suggest a potential contribution of GABApre neurons to the deficits in presynaptic inhibition observed in dystonia.
No associated publication
Specimen part
View SamplesMuscle atrophy F-box (MAFbx/atrogin-1), an E3 ubiquitin ligase, is a crucial mediator of skeletal muscle atrophy and cardiac hypertrophy in response to pressure overload and exercise.
No associated publication
Specimen part
View SamplesAppropriate regulation of hematopoietic stem cell (HSC) self-renewal is critical for the maintenance of life long hematopoiesis. However, long-term repeated cell divisions induce the accumulation of DNA damage, especially at telomere, significantly compromises HSC function. Therefore, shelterin elements Pot1a is required to prevent DNA damage response at telomeres in order to maintain their function.
The telomere binding protein Pot1 maintains haematopoietic stem cell activity with age.
Sex, Specimen part
View SamplesAppropriate regulation of hematopoietic stem cell (HSC) self-renewal is critical for the maintenance of life long hematopoiesis. However, long-term repeated cell divisions induce the accumulation of DNA damage, especially at telomere, significantly compromises HSC function. Therefore, shelterin elements Pot1a is required to prevent DNA damage response at telomeres in order to maintain their function.
No associated publication
Sex, Specimen part
View SamplesTumor recurrence and metastasis remain unavoidable due to a distinct tumor subpopulation known as cancer stem cells (CSCs). To explore the unique cell types contribute to colorectal cancer (CRC) progression, we profiled 831 single cells by simultaneous analysis of RNA sequencing (scRNA-seq) and telomere length in the same cell. Specific markers CD44, CD133 and LGR5 were used to enrich. We find small subpopulations with special features including quiescent CSCs, and epithelial lineage cancer cells (EPCs). Those quiescent CSCs have distinct features including higher level of pluripotency and Wnt signature, and shorter telomeres. Lineage tracing analysis showed that quiescent CSCs could plasticized and generate to epithelial lineage cancer cells with high proliferation and telomeres elongation, and these cells could also transform to each other. New marker genes for CSCs were identified including PROX1, TNFRSF19 and SMOC2. Survival analysis revealed that higher signatures of CSCs and EPCs predicts poor clinical outcome in CRC patients and could be a prognostic biomarkers. These findings provide insight into molecular classification of colorectal cancers and telomere function in CSCs.
No associated publication
Sex, Age, Specimen part
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