Loss of PDEF, a prostate-derived Ets factor is associated with aggressive phenotype of prostate cancer: regulation of MMP 9 by PDEF
Authors: Binod Kumar
Hari K Koul
Sweaty Koul
Thomas R Johnson
Sarah Venezia
Randall B Meacham
Paul D Maroni
Lakshmipathi Khandrika
Journal: Molecular Cancer (2010)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Prostate-derived Ets factor (PDEF); prostate cancer; metastasis; aggressive phenotype; Gleason Grade
Affiliations: Division of Urology, Department of Surgery, University of Colorado Denver School of Medicine, Denver Veterans Administrative Medical Center, and University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA.

Abstract:  Background: Prostate-derived Ets factor (PDEF) is expressed in tissues of high epithelial content including prostate, although its precise function has not been fully established. Conventional therapies produce a high rate of cure for patients with localized prostate cancer, but there is, at present, no effective treatment for intervention in metastatic prostate cancer. These facts underline the need to develop new approaches for early diagnosis of aggressive prostate cancer patients, and mechanism based anti-metastasis therapies that will improve the outlook for hormone-refractory prostate cancer. In this study we evaluated role of prostate-derived Ets factor (PDEF) in prostate cancer. Results: We observed decreased PDEF expression in prostate cancer cell lines correlated with increased aggressive phenotype, and complete loss of PDEF protein in metastatic prostate cancer cell lines. Loss of PDEF expression was confirmed in high Gleason Grade prostate cancer samples by immuno-histochemical methods. Reintroduction of PDEF profoundly affected cell behavior leading to less invasive phenotypes in three dimensional cultures. In addition, PDEF expressing cells had altered cell morphology, decreased FAK phosphorylation and decreased colony formation, cell migration, and cellular invasiveness. In contrast PDEF knockdown resulted in increased migration and invasion as well as clonogenic activity. Our results also demonstrated that PDEF downregulated MMP9 promoter activity, suppressed MMP9 mRNA expression, and resulted in loss of MMP9 activity in prostate cancer cells. These results suggested that loss of PDEF might be associated with increased MMP9 expression and activity in aggressive prostate cancer. To confirm results we investigated MMP9 expression in clinical samples of prostate cancer. Results of these studies show increased MMP9 expression correlated with advanced Gleason grade. Taken together our results demonstrate decreased PDEF expression and increased MMP9 expression during the transition to aggressive prostate cancer. Conclusions: These studies demonstrate for the first time negative regulation of MMP9 expression by PDEF, and that PDEF expression was lost in aggressive prostate cancer and was inversely associated with MMP9 expression in clinical samples of prostate cancer. Based on these exciting results, we propose that loss of PDEF along with increased MMP9 expression should serve as novel markers for early detection of aggressive prostate cancer. 

Retracted: Yes

PubPeer comments:
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 Copy pasted from https: mcr.aacrjournals.org content 19 6 1096 :  Editor s Note: Focal Adhesion Kinase Controls Aggressive Phenotype of Androgen-Independent Prostate Cancer. The Molecular Cancer Research editors are publishing this note to alert readers to concerns about this article [1]. An institutional investigation suggested that the images used in this article above the first and fourth bars in Fig. 5F to represent DU 145 cells appear to have been reused in a Molecular Cancer article [2] above the fifth and sixth bars, respectively, in Fig. 4D to represent PC-3 cells. Original research records related to these concerns were not available during the institutional investigation; therefore, the institution was not able to determine the relation of the images to the experiments described in this article [1]. Moreover, an internal journal investigation could not dismiss the possibility that the images in question were reused as described. Because a satisfactorily corrected figure could not be provided, the editors are publishing this note to alert readers to these concerns. Published June 2021. [1] Johnson TR, Khandrika L, Kumar B, Venezia S, Koul S, Chandhoke R, et al. Focal adhesion kinase controls aggressive phenotype of androgen-independent prostate cancer. Mol Cancer Res 2008;6:1639u201348. [2] Johnson TR, Koul S, Kumar B, Khandrika L, Venezia S, Maroni PD, et al. Loss of PDEF, a prostate-derived Ets factor is associated with aggressive phenotype of prostate cancer: regulation of MMP 9 by PDEF. Mol Cancer 2010;9:148. See https: pubpeer.com publications A48EEAA373336EBFC0FE56D622696D (ref [1]). See for backgrounds https: retractionwatch.com 2021 07 21 journals-retract-papers-following-publication-of-university-investigation-by-retraction-watch , 
 2021 retraction. https: molecular-cancer.biomedcentral.com articles 10.1186 s12943-021-01402-x Retraction Note to: Mol Cancer 9, 148 (2010) https: doi.org 10.1186 1476-4598-9-148 The Editor-in-Chief has retracted this article. After publication concerns were raised that the images above the last two bars in Fig. 4D are identified as PC3 cells, whereas in [1] the same images in Fig. 5F above the first and fourth bars are identified as DU145 cells. An investigation by the University of Colorado at Denver was unable to establish the veracity of these images as the original data were not available. The Editor-in-Chief no longer has confidence in the data presented. Hari K Koul, Paul D Maroni, Lakshmipathi Khandrika, Randall B Meacham and Binod Kumar agree with this retraction. Sweaty Koul has not responded to any correspondence from the Editor-in-Chief or Publisher about this retraction. The Editor-in-Chief was not able to obtain a current email address for Thomas R. Johnson and Sarah Venezia. Reference 1. Johnson TR, Khandrika L, Kumar B, Venezia S, Koul S, Chandhoke R, et al. Focal adhesion kinase controls aggressive phenotype of androgen-independent prostate Cancer. Mol Cancer Res. 2008;6(10):1639u201348. https: doi.org 10.1158 1541-7786.MCR-08-0052. ,