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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.

AbstractBACKGROUND:
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.
CONCLUSION:
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.
AuthorsLeslie Oleksowicz, Yin Liu, R Bruce Bracken, Krishnanath Gaitonde, Barbara Burke, Paul Succop, Linda Levin, Zhongyun Dong, Shan Lu
JournalThe Prostate (Prostate) Vol. 72 Issue 10 Pg. 1140-9 (Jul 1 2012) ISSN: 1097-0045 [Electronic] United States
PMID22127954 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Wiley Periodicals, Inc.
Chemical References
  • Biomarkers, Tumor
  • Neuregulin-1
  • heregulin alpha
  • EGFR protein, human
  • Receptor, Epidermal Growth Factor
  • Receptor, ErbB-2
  • Group II Phospholipases A2
  • PLA2G2A protein, human
Topics
  • Aged
  • Aged, 80 and over
  • Animals
  • Biomarkers, Tumor (blood, genetics)
  • Cell Line, Tumor
  • Gene Targeting (trends)
  • Group II Phospholipases A2 (blood, genetics, secretion)
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Neuregulin-1 (biosynthesis, genetics)
  • Prognosis
  • Prostatic Neoplasms (blood, diagnosis, enzymology)
  • Receptor, Epidermal Growth Factor (biosynthesis, genetics)
  • Receptor, ErbB-2 (biosynthesis, genetics)
  • Signal Transduction (physiology)

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