Vav3 oncogene is involved in regulation of secretory phospholipase A2-IIa expression in prostate cancer

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 (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.

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“…IHC analysis showed an elevated expression of sPLA2-IIa in tumor specimens (23,28) (Fig. 3A), confirming the findings of others (19–21).…”

Section: Resultssupporting

confidence: 88%

“…We were the first to demonstrate that prostate cancer cells secreted sPLA2-IIa and EGF stimulated sPLA2-IIa expression and secretion via EGFR/HER2-PI3K-Akt-NF-kB signaling (23,28). In the current study, we further explored the underlying mechanism of sPLA2-IIa overexpression and the potential role of sPLA2-IIa in prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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“…We recently reported that elevated signaling of the HER/HER2-PI3K-Akt-NF-kB pathway contributes to sPLA2-IIa overexpression and secretion in prostate cancer cells [17,22,23]. We confirmed that sPLA2-IIa secreted by cancer cells into the circulation to a detecTable level in mice carrying xenograft human tumor.…”

Section: Introductionsupporting

confidence: 76%

Plasma secretory phospholipase A2-IIa as a potential biomarker for lung cancer in patients with solitary pulmonary nodules

et al. 2011

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BackgroundFive-year survival for lung cancer has remained at 16% over last several decades largely due to the fact that over 50% of patients are diagnosed with locally-advanced or metastatic disease. Diagnosis at an earlier and potentially curable stage is crucial. Solitary pulmonary nodules (SPNs) are common, but the difficulty lies in the determination of which SPN is malignant. Currently, there is no convenient and reliable biomarker effective for early diagnosis. Secretory phospholipase A2-IIa (sPLA2-IIa) is secreted into the circulation by cancer cells and may allow for an early detection of lung cancer.MethodsPlasma samples from healthy donors, patients with only benign SPN, and patients with lung cancer were analyzed. Expression of sPLA2-IIa protein in lung cancer tissues was also determined.ResultsWe found that the levels of plasma sPLA2-IIa were significantly elevated in lung cancer patients. The receiver operating characteristic curve analysis, comparing lung cancer patients to patients with benign nodules, revealed an optimum cutoff value for plasma sPLA2-IIa of 2.4 ng/ml to predict an early stage cancer with 48% sensitivity and 86% specificity and up to 67% sensitivity for T2 stage lung cancer. Combined sPLA2-IIa, CEA, and Cyfra21.1 tests increased the sensitivity for lung cancer prediction. High level of plasma sPLA2-IIa was associated with a decreased overall cancer survival. sPLA2-IIa was overexpressed in almost all non-small cell lung cancer and in the majority of small cell lung cancer by immunohistochemistry analysis.ConclusionOur finding strongly suggests that plasma sPLA2-IIa is a potential lung biomarker to distinguish benign nodules from lung cancer and to aid lung cancer diagnosis in patients with SPNs.

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“…An increasing body of evidence support the notion that plasma sPLA2-IIa potentially is a novel therapeutic target: i) sPLA2-IIa stimulates tumor cell growth in prostate cancer (20,33,34), colon cancer (35), skin (36), and brain cancer (37,38), while inhibition of eicosanoid signaling leads to cancer regression (39,40); ii) we found that sPLA2-IIa activates HER/HER2-elicited signaling and sPLA2-IIa promoter and stimulates cancer cell growth in a positive feedback manner (20,25,41); iii) sPLA2-IIa stimulates production of vascular endothelial growth factor (VEGF) (42) and nitric oxide synthase expression, contributing to inflammation and angiogenesis in tumors (43,44); iv) sPLA2-IIa abrogates TNF-α-induced apoptosis and compromises immune surveillance function (45); v) sPLA2-IIa stimulates eicosanoid biosynthesis and inflammation contributing to cancer progression (46); vi) through interaction with yet to be identified receptor (18,47), sPLA2-IIa stimulates EGFR-, MAPK-, PI3K/Akt-, NF-κB-mediated cell growth and survival signaling pathways (44,48); and vii) knockdown of secretory phospholipase A2 IIa reduces lung cancer growth both in vitro and in vivo (49). …”

Section: Discussionmentioning

confidence: 85%

Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells

Dong

Meller

Succop

et al. 2014

International Journal of Oncology

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Lung cancer is the leading cause of cancer death worldwide. There is an urgent need for early diagnostic tools and novel therapies in order to increase lung cancer survival. Secretory phospholipase A2 group IIa (sPLA2-IIa) is involved in inflammation, tumorigenesis and metastasis. We were the first to uncover that cancer cells secrete sPLA2-IIa. sPLA2-IIa is overexpressed in almost all specimens of human lung cancers examined and is significantly elevated in the plasma of lung cancer patients. High levels of plasma sPLA2-IIa are significantly associated with advanced stage and decreased overall cancer survival. In this study, we further showed that elevated HER/HER2-PI3K-Akt-NF-κB signaling contributes to sPLA2-IIa overexpression in lung cancer cells. sPLA2-IIa in turn phosphorylates and activates HER2 and HER3 in a time- and dose-dependent manner in lung cancer cells. The structure and sequence-based docking analysis revealed that sPLA2-IIa β hairpin shares structural similarity with the corresponding EGF hairpin. sPLA2-IIa forms an extensive interface with EGFR and brings the two lobes of EGFR into an active conformation. sPLA2-IIa also enhances the NF-κB promoter activity. Anti-sPLA2-IIa antibody, but not the small molecule sPLA2-IIa inhibitor LY315920, significantly inhibits sPLA2-IIa-induced activation of NF-κB promoter. Our findings support the notion that sPLA2-IIa functions as a ligand for the EGFR family of receptors leading to an elevated HER/HER2-elicited signaling. Plasma sPLA2-IIa can potentially serve as lung cancer biomarker and sPLA2-IIa is a potential therapeutic target against lung cancer.

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Vav3 oncogene is involved in regulation of secretory phospholipase A2-IIa expression in prostate cancer

Cited by 5 publications

References 16 publications

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

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

Plasma secretory phospholipase A2-IIa as a potential biomarker for lung cancer in patients with solitary pulmonary nodules

Secretory phospholipase A2-IIa upregulates HER/HER2-elicited signaling in lung cancer cells

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