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YB-1 and MTA1 protein levels and not DNA or mRNA alterations predict for prostate cancer recurrence.

Sheridan CM, Grogan TR, Nguyen HG, Galet C, Rettig MB, Hsieh AC, Ruggero D - Oncotarget (2015)

Bottom Line: Remarkably, protein abundance, but not genomic or transcriptional alterations of YB-1 and MTA1, is predictive of disease recurrence, exhibiting a dose-dependent effect on time to PSA recurrence, an indicator of tumor relapse.Importantly, YB-1 and MTA1 protein levels significantly increase the predictive capacity of a clinical model for prostate cancer recurrence.These findings demonstrate that protein abundance of YB-1 and MTA1, irrespective of DNA or mRNA status, can predict for prostate cancer relapse and uncover a vast underappreciated repository of biomarkers regulated at the level of protein expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California, San Francisco, CA, USA.

ABSTRACT
Attempts to identify biomarkers to detect prostate tumorigenesis, and thus minimize prostate cancer progression and inform treatment decisions have primarily focused on alterations at the DNA and mRNA levels, ignoring alterations at the level of protein synthesis control. We have previously shown that the PI3K-AKT-mTOR pathway, frequently deregulated in prostate cancer, specifically induces the synthesis of proteins that contribute to metastasis, most notably YB-1 and MTA1, without altering mRNA levels thereby demonstrating the importance of translation control in driving the expression of these genes in cancer.Here, we analyze genomic sequencing and mRNA expression databases, as well as protein expression employing an annotated tissue microarray generated from 332 prostate cancer patients with 15 years of clinical follow-up to determine the combined prognostic capability of YB-1 and MTA1 alterations in forecasting prostate cancer outcomes. Remarkably, protein abundance, but not genomic or transcriptional alterations of YB-1 and MTA1, is predictive of disease recurrence, exhibiting a dose-dependent effect on time to PSA recurrence, an indicator of tumor relapse. Moreover, high protein levels of YB-1 and MTA1 are associated with a 3-fold increased risk for requiring future hormone therapy or radiation therapy. Importantly, YB-1 and MTA1 protein levels significantly increase the predictive capacity of a clinical model for prostate cancer recurrence. These findings demonstrate that protein abundance of YB-1 and MTA1, irrespective of DNA or mRNA status, can predict for prostate cancer relapse and uncover a vast underappreciated repository of biomarkers regulated at the level of protein expression.

No MeSH data available.


Related in: MedlinePlus

YB-1 and MTA1 protein levels in adjacent normal, prostatic intraepithelial neoplasia (PIN), and cancer samples from WLA VA patient cohort(A) Representative images of adjacent normal, PIN, and prostate cancer tissues stained for YB-1 or MTA1. (B) Mean fluorescence intensity (MFI) of YB-1 in adjacent normal, PIN, and prostate cancer tissues (* P < 0.001, ** P < 0.001, *** P = 0.014, error bars = 95% confidence interval) (C) Mean fluorescence intensity (MFI) of MTA1 in adjacent normal, PIN, and prostate cancer tissues (* P = 0.002, ** P = 0.008, n.s. = not statistically significant, error bars = 95% confidence interval).
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Figure 1: YB-1 and MTA1 protein levels in adjacent normal, prostatic intraepithelial neoplasia (PIN), and cancer samples from WLA VA patient cohort(A) Representative images of adjacent normal, PIN, and prostate cancer tissues stained for YB-1 or MTA1. (B) Mean fluorescence intensity (MFI) of YB-1 in adjacent normal, PIN, and prostate cancer tissues (* P < 0.001, ** P < 0.001, *** P = 0.014, error bars = 95% confidence interval) (C) Mean fluorescence intensity (MFI) of MTA1 in adjacent normal, PIN, and prostate cancer tissues (* P = 0.002, ** P = 0.008, n.s. = not statistically significant, error bars = 95% confidence interval).

Mentions: Given that YB-1 and MTA1 are translationally regulated mRNAs [5], we hypothesized that differences could be observed at the protein level between normal, pre-invasive prostatic intraepithelial neoplasia (PIN), and prostate cancer tissues despite the lack of alterations at the DNA and mRNA levels. To this end, tissue microarrays were generated using adjacent normal tissue, PIN, and prostatic adenocarcinoma gathered from patients who underwent radical prostatectomy between 1991-2003 at the West Los Angeles Veteran's Affair Medical Center (Table 1). These arrays were stained with YB-1 and MTA1-specific antibodies, imaged using semi-automated high-throughput platforms, and quantified in an unbiased manner. By utilizing this quantitative immunofluorescence technique, we were able to measure the entire spectrum of YB-1 and MTA1 protein expression, from minimally detectable to high levels within each tissue sample. The staining pattern of YB-1 was predominantly cytoplasmic in adjacent normal prostate tissue, PIN, and cancer, which is consistent with its function in regulating the translation of distinct mRNA networks (Figure 1A) [9]. YB-1 protein levels increased in a step-wise manner from normal prostate epithelium to cancer (Figures 1A, 1B, Supplementary Material 2) suggesting a very early requirement for YB-1 in prostate tumorigenesis. In contrast, MTA1 was predominantly nuclear in all three types of tissue (Figure 1A), consistent with its function as a dynamic regulator of chromatin structure [11]. Mean MTA1 levels were nearly equivalent between adjacent normal tissue and PIN, however, PIN exhibited a greater range of MTA1 expression compared to adjacent normal prostate epithelium (Figures 1A, 1C, Supplementary Material 2). In cancer, MTA1 levels are significantly upregulated compared to adjacent normal prostate tissue and PIN (Figures 1A, 1C). Together, this analysis reveals significant increases in YB-1 and MTA1 protein levels throughout prostate cancer pathogenesis, which were not observed at the DNA or RNA levels. Increases in protein synthesis rates likely account for the increase of YB-1 and MTA1 protein levels observed and are consistent with the observation that they are translationally regulated mRNAs [5]. Thus, translationally regulated mRNAs such as YB-1 and MTA1 may serve as biomarkers whose expression trend with the natural history of prostate cancer development and progression.


YB-1 and MTA1 protein levels and not DNA or mRNA alterations predict for prostate cancer recurrence.

Sheridan CM, Grogan TR, Nguyen HG, Galet C, Rettig MB, Hsieh AC, Ruggero D - Oncotarget (2015)

YB-1 and MTA1 protein levels in adjacent normal, prostatic intraepithelial neoplasia (PIN), and cancer samples from WLA VA patient cohort(A) Representative images of adjacent normal, PIN, and prostate cancer tissues stained for YB-1 or MTA1. (B) Mean fluorescence intensity (MFI) of YB-1 in adjacent normal, PIN, and prostate cancer tissues (* P < 0.001, ** P < 0.001, *** P = 0.014, error bars = 95% confidence interval) (C) Mean fluorescence intensity (MFI) of MTA1 in adjacent normal, PIN, and prostate cancer tissues (* P = 0.002, ** P = 0.008, n.s. = not statistically significant, error bars = 95% confidence interval).
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Figure 1: YB-1 and MTA1 protein levels in adjacent normal, prostatic intraepithelial neoplasia (PIN), and cancer samples from WLA VA patient cohort(A) Representative images of adjacent normal, PIN, and prostate cancer tissues stained for YB-1 or MTA1. (B) Mean fluorescence intensity (MFI) of YB-1 in adjacent normal, PIN, and prostate cancer tissues (* P < 0.001, ** P < 0.001, *** P = 0.014, error bars = 95% confidence interval) (C) Mean fluorescence intensity (MFI) of MTA1 in adjacent normal, PIN, and prostate cancer tissues (* P = 0.002, ** P = 0.008, n.s. = not statistically significant, error bars = 95% confidence interval).
Mentions: Given that YB-1 and MTA1 are translationally regulated mRNAs [5], we hypothesized that differences could be observed at the protein level between normal, pre-invasive prostatic intraepithelial neoplasia (PIN), and prostate cancer tissues despite the lack of alterations at the DNA and mRNA levels. To this end, tissue microarrays were generated using adjacent normal tissue, PIN, and prostatic adenocarcinoma gathered from patients who underwent radical prostatectomy between 1991-2003 at the West Los Angeles Veteran's Affair Medical Center (Table 1). These arrays were stained with YB-1 and MTA1-specific antibodies, imaged using semi-automated high-throughput platforms, and quantified in an unbiased manner. By utilizing this quantitative immunofluorescence technique, we were able to measure the entire spectrum of YB-1 and MTA1 protein expression, from minimally detectable to high levels within each tissue sample. The staining pattern of YB-1 was predominantly cytoplasmic in adjacent normal prostate tissue, PIN, and cancer, which is consistent with its function in regulating the translation of distinct mRNA networks (Figure 1A) [9]. YB-1 protein levels increased in a step-wise manner from normal prostate epithelium to cancer (Figures 1A, 1B, Supplementary Material 2) suggesting a very early requirement for YB-1 in prostate tumorigenesis. In contrast, MTA1 was predominantly nuclear in all three types of tissue (Figure 1A), consistent with its function as a dynamic regulator of chromatin structure [11]. Mean MTA1 levels were nearly equivalent between adjacent normal tissue and PIN, however, PIN exhibited a greater range of MTA1 expression compared to adjacent normal prostate epithelium (Figures 1A, 1C, Supplementary Material 2). In cancer, MTA1 levels are significantly upregulated compared to adjacent normal prostate tissue and PIN (Figures 1A, 1C). Together, this analysis reveals significant increases in YB-1 and MTA1 protein levels throughout prostate cancer pathogenesis, which were not observed at the DNA or RNA levels. Increases in protein synthesis rates likely account for the increase of YB-1 and MTA1 protein levels observed and are consistent with the observation that they are translationally regulated mRNAs [5]. Thus, translationally regulated mRNAs such as YB-1 and MTA1 may serve as biomarkers whose expression trend with the natural history of prostate cancer development and progression.

Bottom Line: Remarkably, protein abundance, but not genomic or transcriptional alterations of YB-1 and MTA1, is predictive of disease recurrence, exhibiting a dose-dependent effect on time to PSA recurrence, an indicator of tumor relapse.Importantly, YB-1 and MTA1 protein levels significantly increase the predictive capacity of a clinical model for prostate cancer recurrence.These findings demonstrate that protein abundance of YB-1 and MTA1, irrespective of DNA or mRNA status, can predict for prostate cancer relapse and uncover a vast underappreciated repository of biomarkers regulated at the level of protein expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California, San Francisco, CA, USA.

ABSTRACT
Attempts to identify biomarkers to detect prostate tumorigenesis, and thus minimize prostate cancer progression and inform treatment decisions have primarily focused on alterations at the DNA and mRNA levels, ignoring alterations at the level of protein synthesis control. We have previously shown that the PI3K-AKT-mTOR pathway, frequently deregulated in prostate cancer, specifically induces the synthesis of proteins that contribute to metastasis, most notably YB-1 and MTA1, without altering mRNA levels thereby demonstrating the importance of translation control in driving the expression of these genes in cancer.Here, we analyze genomic sequencing and mRNA expression databases, as well as protein expression employing an annotated tissue microarray generated from 332 prostate cancer patients with 15 years of clinical follow-up to determine the combined prognostic capability of YB-1 and MTA1 alterations in forecasting prostate cancer outcomes. Remarkably, protein abundance, but not genomic or transcriptional alterations of YB-1 and MTA1, is predictive of disease recurrence, exhibiting a dose-dependent effect on time to PSA recurrence, an indicator of tumor relapse. Moreover, high protein levels of YB-1 and MTA1 are associated with a 3-fold increased risk for requiring future hormone therapy or radiation therapy. Importantly, YB-1 and MTA1 protein levels significantly increase the predictive capacity of a clinical model for prostate cancer recurrence. These findings demonstrate that protein abundance of YB-1 and MTA1, irrespective of DNA or mRNA status, can predict for prostate cancer relapse and uncover a vast underappreciated repository of biomarkers regulated at the level of protein expression.

No MeSH data available.


Related in: MedlinePlus