title: A RTK-based functional RNAi screen reveals determinants of PTX-3 expression.
abstract: OBJECTIVE
  The aim of the present study was to explore the role of receptor tyrosine kinases (RTKs) in the regulation of expression of PTX-3, a protector in atherosclerosis.
  
  
  METHODS
  Human monocytic U937 cells were infected with a shRNA lentiviral vector library targeting human RTKs upon LPS stimuli and PTX-3 expression was determined by ELISA analysis. The involvement of downstream signaling in the regulation of PTX-3 expression was analyzed by both Western blotting and ELISA assay.
  
  
  RESULTS
  We found that knocking down of ERBB2/3, EPHA7, FGFR3 and RET impaired PTX-3 expression without effects on cell growth or viability. Moreover, inhibition of AKT, the downstream effector of ERBB2/3, also reduced PTX-3 expression. Furthermore, we showed that FGFR3 inhibition by anti-cancer drugs attenuated p38 activity, in turn induced a reduction of PTX-3 expression.
  
  
  CONCLUSIONS
  Altogether, our study demonstrates the role of RTKs in the regulation of PTX-3 expression and uncovers a potential cardiotoxicity effect of RTK inhibitor treatments in cancer patients who have symptoms of atherosclerosis or are at the risk of atherosclerosis.
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital affiliated to Shanghai JiaoTong University, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Liu
authors.forename: Xin-Kai
authors.initials: XK
authors.lastname: Qu
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Fang
mesh_terms: D050197:Atherosclerosis / Q000378:metabolism; D002097:C-Reactive Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D020794:Receptor Protein-Tyrosine Kinases; D017468:Receptors, Fibroblast Growth Factor; D000683:Serum Amyloid P-Component; D048051:p38 Mitogen-Activated Protein Kinases; D000099153:Pentraxins
keywords: PTX-3; RNAi screening; RTKs; atherosclerosis; cardiotoxicity; target therapy