Post-Transcriptional Regulation of Urokinase-type Plasminogen Activator Receptor Expression in Lipopolysaccharide-induced Acute Lung Injury

Bhandary, Yashodhar P.; Velusamy, Thirunavukkarasu; Shetty, Praveenkumar; Shetty, Rashmi S.; Idell, Steven; Cines, Douglas B.; Jain, Deepika; Bdeir, Khalil; Abraham, Edward; Tsuruta, Yuko; Shetty, Sreerama

doi:10.1164/rccm.200712-1787oc

Cited by 33 publications

(33 citation statements)

References 49 publications

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“…It binds the uPAR 3′UTR and increases uPAR expression by enhancing uPAR mRNA stability (Bhandary et al, 2009;Shetty, 2005). By comparing the expression of metastasisassociated genes, we found that Akt activation is markedly different between MDA-MB-435 and LvBr2 cells.…”

Section: Discussionmentioning

confidence: 83%

MicroRNA-146a Suppresses Metastatic Activity in Brain Metastasis

Hwang

Seol

Park

et al. 2012

Molecules and Cells

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Primary lung tumors, breast tumors, and melanoma metastasize mainly in the brain where therapy is limited to surgery and radiation. To investigate the molecular basis of brain metastases, we isolated brain-trophic metastatic MDA-MB-435-LvBr2 (LvBr2) cells via left ventricle (LV) injection of MDA-MB-435 cells into immunodeficiency (NOD/ SCID) mice. Whereas parent MDA-MB-435 cells displayed an elongated morphology, LvBr2 cells were round and displayed an aggregated distribution. LvBr2 cells expressed lower β-catenin levels and higher heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) levels than parental cells. Since microRNAs are known to play an important role in cancer progression including metastasis, we screened microRNAs expressed specifically in brain metastases. MicroRNA-146a was almost undetectable in LvBr2 cells and highly expressed in the parental cells. Overexpression of miR-146a increased β-catenin expression and suppressed the migratory and invasive activity of LvBr2 cells. The miR-146a-elicited decrease in hnRNPC in turn lowered the expression of MMP-1, uPA, and uPAR and inhibited the migratory and invasive activity of LvBr2 cells. Taken together, our findings indicate that miR-146a is virtually absent from brain metastases and can suppress their metastatic potential including their migratory and invasive activities associated with upregulation of β-catenin and downregulation of hnRNPC.

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Section: Discussionmentioning

confidence: 83%

MicroRNA-146a Suppresses Metastatic Activity in Brain Metastasis

Hwang

Seol

Park

et al. 2012

Molecules and Cells

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“…Transgenic mice with a deletion in the uPA gene (uPA 2/2 ) and control mice on the same genetic background (C57B6/129) were described earlier (15). The mice were kept on a 12:12 hour light-dark cycle with free access to food and water.…”

Section: Micementioning

confidence: 99%

“…Extracts from mouse lungs were prepared as described (15,18). Briefly, mouse lungs were separated into small pieces with fine scissors and rinsed three times with PBS.…”

Section: Preparation Of Crude Extract From Mouse Lung and Western Blomentioning

confidence: 99%

“…Five-micrometer sections cut from paraffinembedded lung tissues were studied for immunohistochemistry (IHC) after incubation with rabbit anti-mouse TF antibody (American Diagnostica, Greenwich, CT) or anti-SPC antibody or normal rabbit IgG as negative control using a commercially available kit (Lab Vision, Fremont, CA) as described before (15).…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Induction of Tissue Factor by Urokinase in Lung Epithelial Cells and in the Lungs

Shetty¹,

Bhandary²,

Shetty³

et al. 2010

Am J Respir Crit Care Med

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Rationale: Urokinase-type plasminogen activator (uPA) regulates extracellular proteolysis in lung injury and repair. Although alveolar expression of uPA increases, procoagulant activity predominates. Objectives: This study was designed to investigate whether uPA alters the expression of tissue factor (TF), the major initiator of the coagulation cascade, in lung epithelial cells (ECs). Methods: Bronchial, primary airway ECs and C57B6 wild-type, uPAdeficient (uPA 2/2 ) mice were exposed to phosphate-buffered saline, uPA, or LPS. Immunohistochemistry, protein, cellular, and molecular techniques were used to assess TF expression and activity. Measurements and Main Results: uPA enhanced TF mRNA and protein expression, and TF-dependent coagulation in lung ECs. uPA-induced expression of TF involves both increased synthesis and enhanced stabilization of TF mRNA. uPA catalytic activity had little effect on induction of TF. By contrast, deletion of the uPA receptor binding growth factor domain from uPA markedly attenuated the induction of TF, suggesting that uPA receptor binding is sufficient for TF induction. Lung tissues of uPA-deficient mice expressed less TF protein and mRNA compared with wild-type mice. In addition, intratracheal instillation of mouse uPA increased TF mRNA and protein expression and accelerated coagulation in lung tissues. uPA 2/2 mice exposed to LPS failed to induce TF. Conclusions: uPA increased TF expression and TF-dependent coagulation in the lungs of mice. We hypothesize that uPA-mediated induction of TF occurs in lung ECs to promote increased fibrin deposition in the airways during acute lung injury.

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“…In another study, investigators studied uPAR expression because of its central role in neutrophil recruitment. This group determined that endotoxin-mediated uPAR expression is mediated through tyrosine phosphorylation of phosphoglycerate kinase and heterogeneous nuclear ribonucleoprotein (29).…”

Section: Pathogenesis Of Ali In Animal Studiesmentioning

confidence: 99%