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Cancers (Basel). 2019 Dec 12;11(12). pii: E1995. doi: 10.3390/cancers11121995.

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.

Author information

1
Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, 6720A Rockledge Drive, Suite 300, Bethesda, MD 20817, USA.
2
John P. Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, MD 20817, USA.
3
Henry Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Dr, Suite 100, Bethesda, MD 20817, USA.
4
Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
5
Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
6
SE-NAP Brain Metastasis Research group, 2nd Department of Pathology, Semmelweis University, 1085 Budapest, Hungary.
7
Department of Urology, Walter Reed National Military Medical Center, Bethesda, MD 20814, USA.

Abstract

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.

KEYWORDS:

AR; PMEPA1; TGF-β; biochemical recurrence; isoform; metastasis; prostate cancer

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