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

ABSTRACT: Urokinase plasminogen activator receptor (PLAUR) has been implicated in a variety of physiological and pathological conditions. The multi-functionality of PLAUR is due to its capacity to interact with many co-receptors to regulate extracellular proteolysis and intracellular signaling. Recent reports are identifying novel functions of PLAUR which were not evident in the past; however, the molecular mechanisms of PLAUR signaling are not completely understood. Here, we have compared the transcriptomes of silencing control (sicon) and PLAUR silenced (PLAURsi) MDA-MB-231 breast cancer cells on treatment with radiation. We isolated RNA from the cells, synthesized cDNA and measured the gene expression changes by microarray. We identified 24 downregulated and 53 upregulated genes, which were significantly (P-value < 0.005) affected by PLAUR silencing. Our analysis revealed 415 canonical pathways and 743 causal disease networks affected on silencing PLAUR. Transcriptomic changes and predicted pathways supported and consolidated some of the earlier understanding in the context of PLAUR signaling; including our recent observations in DNA damage and repair process. In addition, we have identified several novel pathways where PLAUR is implicated.

SUBMITTER: Narayanaswamy PB

PROVIDER: S-EPMC5731897 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Narayanaswamy Pavan B PB Baral Tapan K TK Haller Hermann H Dumler Inna I Acharya Kshitish K Kiyan Yulia Y

Oncotarget 20170928 60

Urokinase plasminogen activator receptor (PLAUR) has been implicated in a variety of physiological and pathological conditions. The multi-functionality of PLAUR is due to its capacity to interact with many co-receptors to regulate extracellular proteolysis and intracellular signaling. Recent reports are identifying novel functions of PLAUR which were not evident in the past; however, the molecular mechanisms of PLAUR signaling are not completely understood. Here, we have compared the transcripto ...[more]

PMID: 29254187

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Project description:IntroductionEndocrine resistance in breast cancer is associated with enhanced metastatic potential and poor clinical outcome, presenting a significant therapeutic challenge. We have established several endocrine insensitive breast cancer lines by shRNA induced depletion of estrogen receptor (ER) by transfection of MCF-7 cells which all exhibit enhanced expression profile of mesenchymal markers with reduction of epithelial markers, indicating an epithelial to mesenchymal transition. In this study we describe their behaviour in response to change in extracellular pH, an important factor controlling cell motility and metastasis.MethodsMorphological changes associated with cell exposure to extracellular alkaline pH were assessed by live cell microscopy and the effect of various ion pumps on this behavior was investigated by pretreatment with chemical inhibitors. The activity and expression profile of key signaling molecules was assessed by western blotting. Cell motility and invasion were examined by scratch and under-agarose assays respectively. Total matrix metalloproteinase (MMP) activity and specifically of MMP2/9 was assessed in conditioned medium in response to brief alkaline pH exposure.ResultsExposure of ER -ve but not ER +ve breast cancer cells to extracellular alkaline pH resulted in cell shrinkage and spherical appearance (termed contractolation); this was reversed by returning the pH back to 7.4. Contractolation was blocked by targeting the Na(+)/K(+) and Na(+)/H(+) pumps with specific chemical inhibitors. The activity and expression profile of key signaling molecules critical for cell adhesion were modulated by the exposure to alkaline pH. Brief exposure to alkaline pH enhanced MMP2/9 activity and the invasive potential of ER -ve cells in response to serum components and epithelial growth factor stimulation without affecting unhindered motility.ConclusionsEndocrine resistant breast cancer cells behave very differently to estrogen responsive cells in alkaline pH, with enhanced invasive potential; these studies emphasise the crucial influence of extracellular pH and caution against indiscriminate application of alkalinising drug therapy.

Dataset Information

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

Publications

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

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