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Analysis of PMEPA1 Isoforms (a and b) as Selective Inhibitors of Androgen and TGF-β Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer

Dysfunctions of androgen/TGF-β signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) inhibits androgen and TGF-β signaling via a negative feedback loop. The loss of PMEPA1 confers resistance to androgen signaling inhibitors and promotes...

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Autores principales: Sharad, Shashwat, Sztupinszki, Zsófia M., Chen, Yongmei, Kuo, Claire, Ravindranath, Lakshmi, Szallasi, Zoltan, Petrovics, Gyorgy, Sreenath, Taduru L., Dobi, Albert, Rosner, Inger L., Srinivasan, Alagarsamy, Srivastava, Shiv, Cullen, Jennifer, Li, Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966662/
https://www.ncbi.nlm.nih.gov/pubmed/31842254
http://dx.doi.org/10.3390/cancers11121995
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author Sharad, Shashwat
Sztupinszki, Zsófia M.
Chen, Yongmei
Kuo, Claire
Ravindranath, Lakshmi
Szallasi, Zoltan
Petrovics, Gyorgy
Sreenath, Taduru L.
Dobi, Albert
Rosner, Inger L.
Srinivasan, Alagarsamy
Srivastava, Shiv
Cullen, Jennifer
Li, Hua
author_facet Sharad, Shashwat
Sztupinszki, Zsófia M.
Chen, Yongmei
Kuo, Claire
Ravindranath, Lakshmi
Szallasi, Zoltan
Petrovics, Gyorgy
Sreenath, Taduru L.
Dobi, Albert
Rosner, Inger L.
Srinivasan, Alagarsamy
Srivastava, Shiv
Cullen, Jennifer
Li, Hua
author_sort Sharad, Shashwat
collection PubMed
description Dysfunctions of androgen/TGF-β signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) inhibits androgen and TGF-β signaling via a negative feedback loop. The loss of PMEPA1 confers resistance to androgen signaling inhibitors and promotes bone metastasis. Conflicting reports on the expression and biological functions of PMEPA1 in prostate and other cancers propelled us to investigate isoform specific functions in prostate cancer (PCa). One hundred and twenty laser capture micro-dissection matched normal prostate and prostate tumor tissues were analyzed for correlations between quantitative expression of PMEPA1 isoforms and clinical outcomes with Q-RT-PCR, and further validated with a The Cancer Genome Atlas (TCGA) RNA-Seq dataset of 499 PCa. Cell proliferation was assessed with cell counting, plating efficiency and soft agar assay in androgen responsive LNCaP and TGF-β responsive PC3 cells. TGF-β signaling was measured by SMAD dual-luciferase reporter assay. Higher PMEPA1-a mRNA levels indicated biochemical recurrence (p = 0.0183) and lower PMEPA1-b expression associated with metastasis (p = 0.0173). Further, lower PMEPA1-b and a higher ratio of PMEPA1-a vs. -b were correlated to higher Gleason scores and lower progression free survival rate (p < 0.01). TGF-β-responsive PMEPA1-a promoted PCa cell growth, and androgen-responsive PMEPA1-b inhibited cancer cell proliferation. PMEPA1 isoforms -a and -b were shown to be promising candidate biomarkers indicating PCa aggressiveness including earlier biochemical relapse and lower disease specific life expectancy via interrupting androgen/TGF-β signaling.
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spelling pubmed-69666622020-02-04 Analysis of PMEPA1 Isoforms (a and b) as Selective Inhibitors of Androgen and TGF-β Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer Sharad, Shashwat Sztupinszki, Zsófia M. Chen, Yongmei Kuo, Claire Ravindranath, Lakshmi Szallasi, Zoltan Petrovics, Gyorgy Sreenath, Taduru L. Dobi, Albert Rosner, Inger L. Srinivasan, Alagarsamy Srivastava, Shiv Cullen, Jennifer Li, Hua Cancers (Basel) Article Dysfunctions of androgen/TGF-β signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) inhibits androgen and TGF-β signaling via a negative feedback loop. The loss of PMEPA1 confers resistance to androgen signaling inhibitors and promotes bone metastasis. Conflicting reports on the expression and biological functions of PMEPA1 in prostate and other cancers propelled us to investigate isoform specific functions in prostate cancer (PCa). One hundred and twenty laser capture micro-dissection matched normal prostate and prostate tumor tissues were analyzed for correlations between quantitative expression of PMEPA1 isoforms and clinical outcomes with Q-RT-PCR, and further validated with a The Cancer Genome Atlas (TCGA) RNA-Seq dataset of 499 PCa. Cell proliferation was assessed with cell counting, plating efficiency and soft agar assay in androgen responsive LNCaP and TGF-β responsive PC3 cells. TGF-β signaling was measured by SMAD dual-luciferase reporter assay. Higher PMEPA1-a mRNA levels indicated biochemical recurrence (p = 0.0183) and lower PMEPA1-b expression associated with metastasis (p = 0.0173). Further, lower PMEPA1-b and a higher ratio of PMEPA1-a vs. -b were correlated to higher Gleason scores and lower progression free survival rate (p < 0.01). TGF-β-responsive PMEPA1-a promoted PCa cell growth, and androgen-responsive PMEPA1-b inhibited cancer cell proliferation. PMEPA1 isoforms -a and -b were shown to be promising candidate biomarkers indicating PCa aggressiveness including earlier biochemical relapse and lower disease specific life expectancy via interrupting androgen/TGF-β signaling. MDPI 2019-12-12 /pmc/articles/PMC6966662/ /pubmed/31842254 http://dx.doi.org/10.3390/cancers11121995 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sharad, Shashwat
Sztupinszki, Zsófia M.
Chen, Yongmei
Kuo, Claire
Ravindranath, Lakshmi
Szallasi, Zoltan
Petrovics, Gyorgy
Sreenath, Taduru L.
Dobi, Albert
Rosner, Inger L.
Srinivasan, Alagarsamy
Srivastava, Shiv
Cullen, Jennifer
Li, Hua
Analysis of PMEPA1 Isoforms (a and b) as Selective Inhibitors of Androgen and TGF-β Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer
title Analysis of PMEPA1 Isoforms (a and b) as Selective Inhibitors of Androgen and TGF-β Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer
title_full Analysis of PMEPA1 Isoforms (a and b) as Selective Inhibitors of Androgen and TGF-β Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer
title_fullStr Analysis of PMEPA1 Isoforms (a and b) as Selective Inhibitors of Androgen and TGF-β Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer
title_full_unstemmed Analysis of PMEPA1 Isoforms (a and b) as Selective Inhibitors of Androgen and TGF-β Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer
title_short Analysis of PMEPA1 Isoforms (a and b) as Selective Inhibitors of Androgen and TGF-β Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer
title_sort analysis of pmepa1 isoforms (a and b) as selective inhibitors of androgen and tgf-β signaling reveals distinct biological and prognostic features in prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966662/
https://www.ncbi.nlm.nih.gov/pubmed/31842254
http://dx.doi.org/10.3390/cancers11121995
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