Transcriptomic pathway analysis of urokinase receptor silenced breast cancer cells: a microarray study

Narayanaswamy, Pavan B.; Baral, Tapan Kumar; Haller, Hermann; Dumler, Inna; Acharya, Kshitish K.; Kiyan, Yulia

doi:10.18632/oncotarget.21351

Cited by 16 publications

(15 citation statements)

References 77 publications

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“…In addition, uPAR acts independently from the proteolytic activity of uPA. Binding of uPA or its catalytically inactive amino terminal fragment to uPAR or uPAR overexpression induces intracellular signaling pathways orchestrating important cellular functions such as proliferation, differentiation, migration, DNA repair ( 1 , 3 , 4 ). Since uPAR is a GPI anchored protein and lacks a transmembrane domain, it relies on interaction with other receptors to transduce signals across cell membrane.…”

Section: Introductionmentioning

confidence: 99%

TLR4 Response to LPS Is Reinforced by Urokinase Receptor

Kiyan

Tkachuk

Rong³

et al. 2020

Front. Immunol.

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GPI-anchored uPAR is the receptor for the extracellular serine protease urokinase-type plasminogen activator (uPA). Though uPAR role in inflammatory processes is documented, underlying mechanisms are not fully understood. In this study we demonstrate that uPAR is a part of Toll-like receptor 4 (TLR4) interactome. Downregulation of uPAR expression resulted in diminished LPS-induced TLR4 signaling, less activation of NFκB, and decreased secretion of inflammatory mediators in myeloid and non-myeloid cells in vitro. In vivo uPAR−/− mice demonstrated better survival, strongly diminished inflammatory response and better organ functions in cecal ligation and puncture mouse polymicrobial sepsis model. Mechanistically, GPI-uPAR and soluble uPAR colocalized with TLR4 on the cell membrane and interacted with scavenger receptor CD36. Our data show that uPAR can interfere with innate immunity response via TLR4 and this mechanism represents a potentially important target in inflammation and sepsis therapy.

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Section: Introductionmentioning

confidence: 99%

TLR4 Response to LPS Is Reinforced by Urokinase Receptor

Kiyan

Tkachuk

Rong³

et al. 2020

Front. Immunol.

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“…31–33 ITGB1 and PLAUR were upregulated, which are markers of blood vessel remodeling. 34–37 The majority of tumorigenesis markers (ALDH1A1, PROM1, NOS2, ERBB2, CXCL8, PLAUR, SNAI1, and ENG) were considerably upregulated. While expression of AXL and LIN28B, cancer stem cell markers, was downregulated; ZEB2, KIT, TWIST1, TWIST2, ABCB5, ALDH1A1, and PROM1 were upregulated.…”

Section: Resultsmentioning

confidence: 99%

Human-derived osteoblast-like cells and pericyte-like cells induce distinct metastatic phenotypes in primary breast cancer cells

Mayo

Bowles

Wubker

et al. 2020

Exp Biol Med (Maywood)

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Approximately 70% of advanced breast cancer patients will develop bone metastases, which accounts for ∼90% of cancer-related mortality. Breast cancer circulating tumor cells (CTCs) establish metastatic tumors in the bone after a close interaction with local bone marrow cells including pericytes and osteoblasts, both related to resident mesenchymal stem/stromal cells (BM-MSCs) progenitors. In vitro recapitulation of the critical cellular players of the bone microenvironment and infiltrating CTCs could provide new insights into their cross-talk during the metastatic cascade, helping in the development of novel therapeutic strategies. Human BM-MSCs were isolated and fractionated according to CD146 presence. CD146+ cells were utilized as pericyte-like cells (PLCs) given the high expression of the marker in perivascular cells, while CD146− cells were induced into an osteogenic phenotype generating osteoblast-like cells (OLCs). Transwell migration assays were performed to establish whether primary breast cancer cells (3384T) were attracted to OLC. Furthermore, proliferation of 3384T breast cancer cells was assessed in the presence of PLC- and OLC-derived conditioned media. Additionally, conditioned media cultures as well as transwell co-cultures of each OLCs and PLCs were performed with 3384T breast cancer cells for gene expression interrogation assessing their induced transcriptional changes with an emphasis on metastatic potential. PLC as well as their conditioned media increased motility and invasion potential of 3384T breast cancer cells, while OLC induced a dormant phenotype, downregulating invasiveness markers related with migration and proliferation. Altogether, these results indicate that PLC distinctively drive 3384T cancer cells to an invasive and migratory phenotype, while OLC induce a quiescence state, thus recapitulating the different phases of the in vivo bone metastatic process. These data show that phenotypic responses from metastasizing cancer cells are influenced by neighboring cells at the bone metastatic niche during the establishment of secondary metastatic tumors.

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“…PLAUR, is known to regulate the ubiquitin proteasome system during DNA damage response and silencing PLAUR impairs the DNA repair process (70). Interestingly in MDA-MB-231 cells and HeLa cells, PLAUR plays a signi cant role in regulating the homologous recombination (HR) DNA repair pathway (71). PLAUR is a potential molecular target for breast cancer owing to its accessibility on the surface of cancer cells (72).…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of CRISPR Cas 9 Mediated Mdig Deletion in Triple Negative Breast Cancer Cells

Thakur

Zhang

Carruthers

et al. 2020

Preprint

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BackgroundWe have identified an environmentally inducible gene, mdig that predicted the overall survival in breast cancer patients. We showed that mdig regulated breast cancer cell growth, motility and invasion partially through DNA and histone methylation. However, we have lacked a comprehensive analysis of the proteomic profile of mdig in triple negative breast cancer cells. MethodsWe applied mass spectrometry to acquire global proteomic and post translational modification analysis for triple negative breast cancer cells MDA-MB-231 that had mdig deleted via CRISPR Cas 9 gene editing. Using label-free bottom up quantitative proteomics, we compared wildtype control (WT) and mdig knockout (KO) MDA-MB-231 cells and identified the proteins and pathways that are significantly altered with mdig deletion. The Ingenuity Pathway Analysis (IPA) platform was further used to explore the signaling pathway networks incorporating differentially expressed proteins. Results904 differentially expressed (p < 0.005) proteins were identified in MDA-MB-231 cells that had mdig deletion. Approximately 30 pathways and networks linked to the pathogenicity of breast cancer and populated by the differentially expressed proteins were either activated or inhibited. IPA established that the differentially expressed proteins have relevant biological actions in cell growth, motility and malignancy. This analysis provides a rich source of potential candidate therapeutic targets with potential prognostic significance in triple negative breast cancer. Data are available via ProteomeXchange with identifier PXD016688.Conclusions These data provide the first insight into protein expression patterns in breast cancer associated with a complete disruption of the mdig gene. Differentially expressed proteins between WT and KO MDA-MB-231 triple negative breast cancer cells provide substantial information regarding key proteins, biological process and pathways that are modulated by mdig and contribute to breast cancer tumorigenicity and invasiveness. Mdig modulated signaling pathways and hub molecules provide novel targets for the development of treatment strategies and breast cancer therapies.

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Transcriptomic pathway analysis of urokinase receptor silenced breast cancer cells: a microarray study

Cited by 16 publications

References 77 publications

TLR4 Response to LPS Is Reinforced by Urokinase Receptor

TLR4 Response to LPS Is Reinforced by Urokinase Receptor

Human-derived osteoblast-like cells and pericyte-like cells induce distinct metastatic phenotypes in primary breast cancer cells

Proteomic Analysis of CRISPR Cas 9 Mediated Mdig Deletion in Triple Negative Breast Cancer Cells

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