title: Secretory phospholipase A2-IIa is a target gene of the HER/HER2-elicited pathway and a potential plasma biomarker for poor prognosis of prostate cancer.
abstract: BACKGROUND
  Our previous study showed that prostate cancer cells overexpress and secrete secretory phospholipases A2 group IIa (sPLA2-IIa) and plasma sPLA2-IIa was elevated in prostate cancer patients. The current study further explored the underlying mechanism of sPLA2-IIa overexpression and the potential role of sPLA2-IIa as a prostate cancer biomarker.
  
  
  METHODS
  Plasma and tissue specimens from prostate cancer patients were analyzed for sPLA2-IIa levels. Regulation of sPLA2-IIa expression by Heregulin-α was determined by Western blot and reporter assay.
  
  
  RESULTS
  We found that Heregulin-α enhanced expression of the sPLA2-IIa gene via the HER2/HER3-elicited pathway. The EGFR/HER2 dual inhibitor Lapatinib and the NF-kB inhibitor Bortezomib inhibited sPLA2-IIa expression induced by Heregulin-α. Heregulin-α upregulated expression of the sPLA2-IIa gene at the transcriptional level. We further confirmed that plasma sPLA2-IIa secreted by mouse bearing human prostate cancer xenografts reached detectable plasma concentrations. A receiver operating characteristic (ROC) analysis of patient plasma specimens revealed that high levels of plasma sPLA2-IIa, with the optimum cutoff value of 2.0 ng/ml, were significantly associated with high Gleason score (8-10) relative to intermediate Gleason score (6-7) prostate cancers and advanced relative to indolent cancers. The area under the ROC curve (area under curve, AUC) was 0.73 and 0.74, respectively.
  
  
  CONCLUSIONS
  We found that Heregulin-α, in addition to EGF, contributes to sPLA2-IIa overexpression in prostate cancer cells. Our findings support the notion that high levels of plasma sPLA2-IIa may serve as a poor prognostic biomarker capable of distinguishing aggressive from indolent prostate cancers, which may improve decision-making and optimize patient management.
authors: Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors: Leslie
authors: L
authors: Oleksowicz
authors: Yin
authors: Y
authors: Liu
authors: R Bruce
authors: RB
authors: Bracken
authors: Krishnanath
authors: K
authors: Gaitonde
authors: Barbara
authors: B
authors: Burke
authors: Paul
authors: P
authors: Succop
authors: Linda
authors: L
authors: Levin
authors: Zhongyun
authors: Z
authors: Dong
authors: Shan
authors: S
authors: Lu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D018390:Gene Targeting / Q000639:trends; D054501:Group II Phospholipases A2 / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D020890:Neuregulin-1 / Q000096:biosynthesis / Q000235:genetics; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000097:blood* / Q000175:diagnosis* / Q000201:enzymology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D054501:Group II Phospholipases A2; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; C117463:heregulin alpha; C512478:EGFR protein, human; C516287:PLA2G2A protein, human