Strong expression of the neuronal transcription factor FOXP2 is linked to an increased risk of early PSA recurrence in ERG fusion-negative cancers

Stumm, Laura; Burkhardt, Lia; Steurer, Stefan; Simon, Ronald; Adam, Meike; Becker, Andreas; Sauter, Guido; Minner, Sarah; Schlomm, Thorsten; Sirma, Hüseyin; Michl, Uwe

doi:10.1136/jclinpath-2012-201335

Cited by 33 publications

(32 citation statements)

References 37 publications

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“…This genomic rearrangements result in an androgen-driven overexpression of ERG in affected cells (33). ERG activation leads to a substantial reprogramming of prostate epithelial cells with altered expression of a multitude of genes, and many prognostic factors have a substantially different impact in ERG-positive and -negative cancers (34)(35)(36)(37). Almost identical expression levels and identical prognostic impact of p62 protein in ERG-positive and -negative cancers argue against a relevant impact of ERG-driven cell reprogramming on p62 gene function.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer

Burdelski

Reiswich

Hube‐Magg

et al. 2015

Clinical Cancer Research

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Purpose: Sequestosome 1 (p62) is a multifunctional adapter protein accumulating in autophagy-defective cells.Experimental Design: To evaluate the clinical impact and relationship with key genomic alterations in prostate cancer, p62 protein levels were analyzed by immunohistochemistry on a tissue microarray containing 12,427 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21, and 6q15 were available from earlier studies.Results: p62 immunostaining was absent in benign prostatic glands but present in 73% of 7,822 interpretable prostate cancers. Strong cytoplasmic p62 staining was tightly linked to high Gleason grade, advanced pathologic tumor (pT) stage, positive nodal status, positive resection margin, and early PSA recurrence (P < 0.0001 each). Increased levels of p62 were significantly linked to TMPRSS2-ERG fusions, both by FISH and immunohistochemical analysis (P < 0.0001 each). For example, moderate or strong p62 immunostaining was seen in 28.5% of cancers with TMPRSS2-ERG fusion detected by FISH and in 23.1% of cancers without such rearrangements (P < 0.0001). Strong p62 staining was significantly linked to the presence of all tested deletions, including PTEN (P < 0.0001), 6q15 (P < 0.0001), 5q21 (P ¼ 0.0002), 3p13 (P ¼ 0.0088), and 6q15 (P < 0.0001), suggesting a link between p62 accumulation and loss of genomic stability. The prognostic role of p62 protein accumulation was striking and independent of Gleason grade, pT stage, pN stage, surgical margin status, and preoperative PSA, regardless of whether preoperative or postoperative parameters were used for modeling.Conclusions: Our study identifies cytoplasmic accumulation of p62 as a strong predictor of an adverse prognostic behavior of prostate cancer independently from established clinicopathologic findings.

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Section: Discussionmentioning

confidence: 99%

Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer

Burdelski

Reiswich

Hube‐Magg

et al. 2015

Clinical Cancer Research

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“…In a recent study, FOXP2 has been suggested to play a role in prostate cancer development. Notably, FOXP2 expression is significantly correlated with tumor aggressiveness, especially in nonfusion type prostate cancer [30]. FOXP2 was reported to play an important role in breast cancer carcinogenesis, depletion of FOXP2 was adequate in promoting tumor initiation, and metastasis in BCCs and repressed FOXP2 expression are closely correlated with poor survival in breast cancer [31].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion

et al. 2015

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Hepatocellular carcinoma (HCC) is a major health concern with a high morbidity and mortality rate worldwide. However, the mechanism underlying hepatocarcinogenesis remains unclear. Forkhead box P2 (FOXP2) has been implicated in various human cancer types. However, the role of FOXP2 in HCC remains unknown. Western blot and immunohistochemistry were used to measure the expression of FOXP2 protein in HCC and adjacent normal tissues in 50 patients. Wound healing and transwell assays were used to determine the cell invasion ability. We showed that the level of FOXP2 was significantly reduced in HCC compared with the adjacent non-tumorous tissue. There was statistical significance between the expression of FOXP2 and vein invasion (P = 0.017), number of tumor nodes (P = 0.028), and AFP (P = 0.033). Low expression of FOXP2 correlated with poor survival. Moreover, wound healing and transwell assays showed that FOXP2 could decrease cell invasion and affect the expression of vimentin and E-cadherin. Our results suggested that FOXP2 expression was downregulated in HCC tumor tissues, and reduced FOXP2 expression was associated with poor overall survival. In addition, downregulation of FOXP2 significantly enhanced cell invasiveness. These findings uncover that FOXP2 might be a new prognostic factor and be closely correlated with HCC cell invasion.

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“…In several of these, a prognostic impact was only seen for ERG-negative, but not for ERG-positive cancers [38,39,40]. The present study demonstrates that GGH belongs to this type of proteins.…”

Section: Discussionmentioning

confidence: 53%

High-Level γ-Glutamyl-Hydrolase (GGH) Expression is Linked to Poor Prognosis in ERG Negative Prostate Cancer

Melling

Rashed

Schroeder

et al. 2017

IJMS

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γ-glutamyl-hydrolase (GGH) is a ubiquitously-expressed enzyme that regulates intracellular folate metabolism for cell proliferation, DNA synthesis, and repair. Employing GGH immunohistochemistry on a tissue microarray with 12,427 prostate cancers, we found that GGH expression was negative to low in normal prostate epithelium, whereas 88.3% of our 10,562 interpretable cancers showed GGH expression. GGH staining was considered as low intensity in 49.6% and as high intensity in 38.6% of cancers. High GGH expression was linked to the TMPRSS2:ERG-fusion positive subset of cancers (p < 0.0001), advanced pathological tumor stage, and high Gleason grade (p < 0.0001 each). Further analysis revealed that these associations were merely driven by the subset of ERG-negative cancers, High GGH expression was weakly linked to early biochemical recurrence in ERG negative cancers (p < 0.0001) and independent from established histo-pathological parameters. Moreover, GGH expression was linked to features of genetic instability, including presence of recurrent deletions at 3p, 5q, 6q, and 10q (PTEN, p ≤ 0.01 each), as well as to accelerated cell proliferation as measured by Ki67 immunohistochemistry (p < 0.0001). In conclusion, the results of our study identify GGH as an ERG subtype specific molecular marker with modest prognostic relevance, which may have clinical relevance if analyzed in combination with other molecular markers.

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Strong expression of the neuronal transcription factor FOXP2 is linked to an increased risk of early PSA recurrence in ERG fusion-negative cancers

Cited by 33 publications

References 37 publications

Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer

Cytoplasmic Accumulation of Sequestosome 1 (p62) Is a Predictor of Biochemical Recurrence, Rapid Tumor Cell Proliferation, and Genomic Instability in Prostate Cancer

Downregulation of FOXP2 promoter human hepatocellular carcinoma cell invasion

High-Level γ-Glutamyl-Hydrolase (GGH) Expression is Linked to Poor Prognosis in ERG Negative Prostate Cancer

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