Abstract
Hypoxia has been associated with malignant progression, metastasis and resistance to therapy. Hence, we studied expression of hypoxia–regulated genes in 100 prostate cancer (CaP) bulk tissues and 71 adjacent benign tissues. We found 24 transcripts significantly overexpressed (p≤0.02). Importantly, higher transcript levels of disc large (drosophila) homolog-associated protein 5 (DLGAP5)/discs large homolog 7 (DLG7)/hepatoma up-regulated protein (HURP), hyaluronan-mediated motility receptor (HMMR) and cyclin B1 (CCNB1) were associated with higher Gleason score and more advanced systemic progression. Since the products of HMMR and CCNB1 have been identified recently as molecular markers of CaP progression, we postulated that DLG7 has prognostic value too. To test this hypothesis, we measured transcript levels for DLG7 in a 150-pair case-control cohort. The cases (progression to systemic disease within six years of surgery) and controls (no progression within eight years) were matched for clinical and pathologic prognostic variables, including grade, stage, and preoperative serum levels of PSA. The overall prognostic ability of DLG7, as tested in receiver operating characteristic analysis was of 0.74 (95% CI, 0.68 to 0.8). Overall, our data indicate that expression of DLG7, a hypoxia-controlled gene, holds prognostic potential in high-risk CaP; this also demonstrates that variation of oxygen tension may constitute a tool for identification of novel biomarkers for CaP.
Highlights
The role of oxygen tension in tumor biology has been unappreciated for a long time; a reason for it has been the relative oxygen-independence of tumors (“the Warburg effect”; ref [1].) that led to the assumption of tumor insensitivity to changes in oxygen tension
We analyzed the 88 hitherto known transcripts regulated by hypoxia-inducible factor 1 (HIF-1) [17]; 500 hypoxia-associated genes identified in cell lines [17]; 23 genes of the conserved core hypoxia signature [18]; twelve HIF-1 targets tested in prostate cancer (CaP) [13]; and 708 genes in the Ingenuity hypoxia signaling pathway [19]
In our samples we identified 24 genes significantly overexpressed in CaP by at least twofold both in bulk tissue and lasercapture microdissection (LCM)–isolated cells (p≤0.02; Table 2)
Summary
The role of oxygen tension (potentia oxygenii, pO2) in tumor biology has been unappreciated for a long time; a reason for it has been the relative oxygen-independence of tumors (“the Warburg effect”; ref [1].) that led to the assumption of tumor insensitivity to changes in oxygen tension. Used markers that predict outcome in men with CaP include the Gleason score, TNM stage, surgical margin status, and preoperative serum levels of prostate-specific antigen (PSA) [6,7,8] Whereas stratification by these variables often effectively predicts the course of disease, tumors with similar biochemical, histopathologic, and clinical conditions can still behave very differently. Expression of hypoxia-regulated molecules [i.e., vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1, osteopontin, lysyl oxidase (LOX) and glucose transporter-1 (GLUT-1)] correlated with pathological status and patient features (reviewed in ref [4].) These studies show the feasibility of identifying biomarkers linking CaP, hypoxia and prognosis and establishing the contribution of hypoxiaassociated genes to CaP progression.
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